Thianaphthene derivatives

ABSTRACT

Compounds of formula (I): ##STR1## (wherein n is 0 or 1, R 1  and R 2  are hydrogen or alkyl, one of A 1  and A 2  is --Z--Y and the other is --W--COOH, where W and Z are alkenylene or alkylene and Y is imidazolyl or pyridyl, and the broken lines represent two single bonds or one single bond and one double bond) and their salts, esters and amides have the ability to inhibit the synthesis of thromboxane A 2  and hence are useful in the treatment of prophylaxis of thrombotic conditions. They may be prepared by introducing an imidazolyl or pyridyl group into the corresponding compound in which Y is replaced by an active group or atom.

This is a division of application Ser. No. 07/007,375 filed Jan. 27,1987 which has issued as U.S. Pat. No. 4,847,272 on July 11, 1989.

BACKGROUND TO THE INVENTION

The present invention relates to a series of thianaphthene derivativeswhich have been found to have certain valuable therapeutic activities.The invention also provides processes for preparing these compounds andmethods of using them.

The compounds of the invention have the ability to inhibit bloodplatelet aggregation and to inhibit the biosynthesis of thromboxane A₂(hereinafter referred to, as is conventional, as "TXA₂ ").

The compounds of the present invention may be regarded as derivatives ofthianaphthene ["The Merck Index", Tenth Edition (1983) monograph 9142],which has the formula (A): ##STR2## In accordance with therecommendations of the International Union of Pure and AppliedChemistry, Commission of Nomenclature of Organic Chemistry, thecompounds of the present invention are named semi-systematically, takingthianaphthene as the parent compound. For the avoidance of doubt, thenumbering system employed herein is that shown on the above formula (A).

TXA₂ plays an important role in inducing blood platelet aggregation, andinhibiting its biosynthesis is believed to reduce the extent of bloodplatelet aggregation, apart from any direct effect the compounds mayhave on such aggregation. It is known that TXA₂ is produced fromprostaglandin endoperoxide PGH₂ via PGG₂. It is known that the activityof TXA₂ is generally opposite to that of PGI₂, which causes vasodilationand prevents platelet aggregation. Accordingly, it has been suggestedthat the balance within the blood between TXA₂ and PGI₂ is a controllingfactor in the development and/or cure of thrombosis. Accordingly, it isdesirable for the treatment or propyhylaxis of thromboembolisms toinhibit selectively the biosynthesis of TXA₂ and thereby to enhance theactivity of PGI₂ (which has an inhibitory effect on plateletaggregation) and also to increase the level of PGI₂ as a result ofaccumulation of PGH₂.

It is believed that an effective inhibitor of the biosynthesis of TXA₂would be of considerable value in the treatment or propyhylaxis of avariety of diseases and disorders associated with the circulatorysystem. It is, however, important that this inhibitory activity shouldnot be accompanied by inhibition of the enzymes responsible for thesynthesis of other prostaglandins.

Various compounds have been proposed for such use. A proposal has beenmade to use certain thianaphthene derivatives for this purpose and thosecompounds disclosed in European Patent Specification No. and thecorresponding U.S. Pat. No. 4,496,752 do exhibit the necessary activity.

We have now discovered that certain thianaphthenes in which the6-membered ring is partially saturated have an outstanding ability toinhibit TXA₂ synthesis which is an order of magnitude or more betterthan that of known compounds which are currently available for thispurpose. Although superficially similar to the compounds of theinvention, the compounds of EP 73663B1 have a fully unsaturated andaromatized thianaphthene ring system. On the contrary, the compounds ofthe invention have a partially saturated 6-membered ring. Thearomaticity of the prior compounds leads to a rigidity of molecularstructure and configuration and a fluidity of electron flow which arenot possessed by the compounds of the present invention and which wouldbe expected to have a major influence on the biological properties ofthe compounds. It is, therefore, surprising that the compounds of theinvention possesses biological properties similar in nature to those ofthe prior compounds, especially since the activity concerned relates tothe inhibition of enzymes, where it would be expected that thedifferences between the prior compounds and the compounds of theinvention would have a substantial influence.

BRIEF SUMMARY OF INVENTION

The compounds of the present invention are those compounds of formula(I): ##STR3## in which:

R¹ and R² are independently selected from the group consisting ofhydrogen atoms. C₁ -C₄ alkyl groups, C₆ -C₁₀ carbocyclic aryl groups andsubstituted C₆ -C₁₀ carbocyclic aryl groups having at least onesubstituent selected from the group consisting of substituents (a);

n is 1 or 2;

one of A¹ and A² represents a group of formula --Z--Y in which Yrepresents an imidazolyl or pyridyl group and Z represents a methylene,ethylene, trimethylene or vinylene group of a methylene, ethylene,trimethylene or vinylene group having at least one substituent selectedfrom the group consisting of substituents (b);

The other of A¹ and A² represents a group of formula --W--COOH, where Wrepresents a direct bond, a methylene group, a methine group (i.e. agroup of formula ═CH-- attached by its double bond to the thianaphthenesystem), an ethylene group, a vinylene group or a substituted methylene,methine, ethylene or vinylene group having at least one substituentselected from the group consisting of substituents (c), provided that Wonly represents said methine group when A¹ represents said group offormula --Z--Y;

A² is at the 5- and 6-position on the thianaphthene system;

each broken line represents a single or double carbon-carbon bondbetween the 4 and 5 or the 6 and 7 positions, provided that, when A² isat the 5-position, there is a single bond between the 6 and 7 positions,and that, when A² is at the 6-position, there is a single bond betweenthe 4 and 5 positions;

substituents (a): C₁ -C₄ alkyl groups, C₁ -C₄ alkoxy groups, C₂ -C₆aliphatic carboxylic acyloxy groups, aromatic carboxylic acyloxy groups,C₂ -C₅ aliphatic carboxylic acylamino groups, aromatic carboxylicacylamino groups, trifluoromethyl groups, halogen atoms, nitro groups,cyano groups, amino groups, C₁ -C₄ alkylamino groups, dialkylaminogroups in which each alkyl part is C₁ -C₄, carboxy groups and esters andamides of said carboxy groups, the aromatic parts of said aromaticacyloxy and aromatic acylamino groups being C₆ -C₁₀ carbocyclic arylgroups which are unsubstituted or have at least one substituent selectedfrom the group consisting of C₁ -C₄ alkyl groups, C₁ -C₄ alkoxy groupsand halogen atoms;

substituents (b): C₁ `C₄ alkyl groups, C₃ -C₆ cycloalkyl groups, C₆ -C₁₀aryl groups, substituted C₆ -C₁₀ aryl groups having at least onesubstituent selected from the group consisting of substituents (a) andheterocyclic groups having from 5 to 10 ring atoms, of which from 1 to 3are hetero-atoms selected from the group consisting of nitrogen, oxygenand sulfur hetero-atoms, said heterocyclic groups being unsubstituted orhaving at least one substituent selected from the group consisting ofsubstituents (a), substituents (c) and oxygen atoms; and

substituents (c): C₁ -C₄ alkyl groups, C₆ -C₁₀ aryl groups andsubstituted C₆ -C₁₀ aryl groups having at least one substituent selectedfrom the group consisting of substituents (a);

and pharmaceutically acceptable salts, amides and esters thereof.

The invention further provides a pharmaceutical composition comprisingan inhibitor of TXA₂ biosynthesis in admixture with a pharmaceuticallyacceptable carrier or diluent, wherein said inhibitor is selected fromthe group consisting of compounds of formula (I) and pharmaceuticallyacceptable esters, amides and salts thereof.

The invention still further provides a method for the treatment orprophylaxis of diseases and disorders arising from an imbalance in thelevel of TXA₂ in an animal, normally mammal, including human being,which comprises administering to said animal an effective amount of aninhibitor of the biosynthesis of TXA₂, wherein said inhibitor isselected from the group consisting of compounds of formula (I) andpharmaceutically acceptable esters, amides and salts thereof.

The invention also provides methods of preparing the compounds offormula (I) and their esters, amides and salts, as described in moredetail hereafter.

DETAILED DESCRIPTION OF THE INVENTION

In more detail, the compounds of the invention may be represented by thetwo formulae (I^(i)) and (I^(ii)): ##STR4## (in which R¹, R², A¹, A² andn are as defined above and the dotted line means a single or doublecarbon-carbon bond) and, more specifically, the compounds may berepresented by the formulae (I^(iii)). (I^(iv)) and (I^(v)): ##STR5##(in which R¹, R², W, Y, Z, n and the dotted and broken lines are asdefined above).

In the compounds of the invention, where R¹, R², substituent (a), thesubstituent on substituted aromatic acyloxy or acylamino groups,substituent (b) or substituent (c) is a C₁ -C₄ alkyl group, this may bea straight or branched chain group and examples include the methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl groups.

Where R¹, R², substituent (b) or substituent (c) represents an arylgroup, this is a carbocyclic aryl group having from 6 to 10, preferably6 or 10, ring carbon atoms and may be unsubstituted or substituted withat least one of the substituents defined above as substituents (a).Examples of such groups include the phenyl, 1-naphthyl and 2-naphthylgroups and such groups having at least one of substituents (a), forexample the o-tolyl, m-tolyl, p-tolyl, o-methoxyphenyl, m-methoxyphenyl,p-methoxyphenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl,o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, o-nitrophenyl,m-nitrophenyl, p-nitrophenyl, o-cyanophenyl, m-cyanophenyl,p-cyanophenyl, 2,4-dichlorophenyl, 3,5-dichlorophenyl,2,4-dimethoxyphenyl, 2,4,6-trimethoxyphenyl, 3,5-dimethoxyphenyl,2,4-dimethylphenyl, 2,4,6-trimethylphenyl, 2-methoxy-4-methylphenyl,o-acetoxyphenyl, p-benzoyloxyphenyl, p-(p-toluoxyloxy)phenyl,p-acetamidophenyl, p-benzamidophenyl, p-trifluoromethylphenyl,3-methyl-1-naphthyl and 7-methyl-1-naphthyl groups.

Where substituent (a) or the substituent on aromatic acyloxy oracylamino groups in a C₁ -C₄ alkoxy group, this is more preferably a C₁-C₃ group and may be a straight or branched chain group. Examplesinclude the methoxy, ethoxy, propoxy, isopropoxy, butoxy and t-butoxygroups.

Where substituent (a) represents a C₂ -C₅ aliphatic carboxylic acyloxygroup, this may be a straight or branched chain group and is preferablyan alkanoyloxy or alkenoyloxy, more preferably alkanoyloxy, group.Examples include the acetoxy, propionyloxy, butyryloxy, isobutyryloxy,valeryloxy, isovaleryloxy and pivaloyloxy groups.

Where substituent (a) represents a carbocyclic aromatic carboxylicacyloxy group, the aromatic part may be as defined above in relation tothe substituted and unsubstituted C₆ -C₁₀ aryl groups, the acyloxy groupbeing an arylcarbonyloxy group. Preferred such groups include thebenzoyloxy, o-toluoyloxy, m-toluoyloxy, p-toluoyloxy, o-anisoyloxy,m-anisoyloxy, p-anisoyloxy, o-chlorobenzoyloxy, m-clorobenzoyloxy andp-chlorobenzoyloxy groups.

Where substituent (a) represents an aliphatic acylamino group, this maybe a straight or branched chain group having from 2 to 5 carbon atomsand is preferably an alkanoylamino or alkenoylamino, more preferablyalkanoylamino, group. Examples include the acetamido, propionylamino,butyrylamino, isobutyrylamino, valeramido, isovaleramido andpivaloylamino groups.

Where substituent (a) represents a carbocyclic aromatic carboxylicacylamino group, the aromatic part may be as exemplified above inrelation to the unsubstituted and substituted C₆ -C₁₀ aryl groups, thegroup being an arylcarbonylamino group. Examples of such groups includethe benzamido, o-toluoylamino, n-toluoylamino, p-toluoylamino,o-anisoylamino, m-anisoylamino, p-anisoylamino, o-chlorobenzamido,m-chlorobenzamido and p-chlorobenzamido groups.

Where substituent (a) represents a halogen atom, this is preferably afluorine, chlorine or bromine atom.

Where substituent (a) is an alkylamino or dialkylamino group, the oreach alkyl part is a C₁ -C₄ alkyl group and examples include themethylamino, ethylamino, propylamino, butylamino, dimethylamino anddiethylamino groups.

Where substituent (a) represents an ester or amide of a carboxy group,this may be as described in more detail hereafter in relation to suchesters and amides.

In the case of substituents (a) and the substituents on aromatic acyloxyand acylamino groups, there is no particular limitation in principle tothe number of such substituents, the only constraints being the number ofsubstitutable positions and possibly steric constraints. Hence, wherethe group to be substituted is a phenyl group, provided steric hindranceis not a problem, and the maximum number of substituents is five. Wherethe group to be substituted is a naphthyl group, again provided sterichindrance is not a problem, the maximum number of substituents is seven.However, more commonly, the number of such substituents will be from 1to 3.

Where substituent (b) represents a cycloalkyl group, this has from 3 to6 ring atoms and may be a cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl group.

Where substituent (b) represents a heterocyclic group, this may be amonocyclic or bicyclic heterocyclic group having from 5 to 10, morepreferably 5 to 6, ring atoms, of which at least one, and preferablyfrom 1 to 3, are hetero-atoms selected from the group consisting ofnitrogen, oxygen and sulfur hetero-atoms. The heterocyclic ring ispreferably, although not necessarily, aromatic in character and it maybe unsubstituted or have at least one substituent selected from thegroup consisting of substituents (a), substituents (b) and oxygen atoms.Examples of such groups include the furyl, thienyl, imidazolyl,thiazolyl, oxazolyl, isoxazolyl, pyridyl, quinolyl, isoquinolyl andindolyl groups, which may be unsubstituted or substituted as definedabove.

Y represents an imidazolyl or pyridyl group, preferably the 1-imidazolylgroup or the 3-pyridyl group.

Z represents the aforementioned methylene, ethylene, trimethylene orvinylene group, any of which may be unsubstituted or may have at leastone substituent selected from the group consisting of substituents (b),as exemplified above.

W may represent a direct bond between the carboxy group and thehydrogenated thianaphthene ring or it may represent a methylene,methine, ethylene or vinylene group, any of which may be unsubstitutedor may have at least one substituent selected from the group consistingof substituents (c), e.g. as exemplified above. Self-evidently, W cannotrepresent a methine group (i.e. a group ═CH-- joined by the double bondto the hydrogenated thianaphthene system) either when A¹ represents saidgroup of formula --W--COOH or when A² represents said group of formula--W--COOH and is attached to a carbon atom which already forms part of aring double bond. In other words, W can only represent a methine groupwhen A² represents said group of formula --W--COOH and both broken linesin formula (I) represent single bonds.

The substituent or substituents represented by R² may be present at anyo the 4, 5, 6 and 7 positions, provided that (in the case of the 5 and 6positions) these are not already occupied by the group represented byA².

Preferred classes of compounds of the present invention are as follows:

1. Compounds of formula (I), (I^(iii)), (I^(iv)) and (I^(v)), definedabove, in which:

A¹, A², Y and the broken and dotted lines are as defined above;

R¹ and R² are independently selected from the group consisting ofhydrogen atoms and C₁ -C₄ alkyl groups;

n is 1;

Z represents a methylene ethylene, trimethylene or vinylene group or amethylene, ethylene, trimethylene or vinylene group having at least onesubstituent selected from the group consisting of substituents (b');

W represents a direct bond or a methylene, methine, ethylene or vinylenegroup; and

substituents (b')

C₁ -C₄ alkyl groups, cyclohexyl groups, phenyl groups and substitutedphenyl groups having at least one substituent selected from the groupconsisting of C₁ -C₄ alkyl groups, C₁ -C₄ alkoxy groups and halogenatoms.

2. Compounds of formula (I^(iii)), defined above, in which:

Y and the dotted lines are as defined above;

R¹ and R² are independently selected from the group consisting ofhydrogen atoms and C₁ -C₄ alkyl groups;

n is 1;

Z represents a methylene, ethylene, trimethylene or vinylene group or amethylene, ethylene, trimethylene or vinylene group having at least onesubstituent selected from the group consisting of substituents (b'),defined above; and

W represents a direct bond or a methylene, methine, ethylene or vinylenegroup.

3. Compounds of formula (I^(iii)), defined above, in which:

Y and the dotted lines are as defined above;

R¹ and R² are independently selected from the group consisting ofhydrogen atoms, methyl groups and ethyl groups;

n is 1;

Z represents a methylene or ethylene group or a methylene or ethylenegroup having at least one substituent selected from the group consistingof substituents (b");

W represents a direct bond; and

substituents (b")

methyl groups, ethyl groups, phenyl groups and substituted phenyl groupshaving at least one substituent selected from the group consisting ofmethyl groups, ethyl groups, methoxy groups, ethoxy groups and halogenatoms.

4. Compounds of formula (I^(iv)), defined above, in which:

Y and the dotted lines are as defined above;

R¹ and R² are independently selected from the group consisting ofhydrogen atoms and C₁ -C₄ alkyl groups;

n is 1;

Z represents a methylene, ethylene, trimethylene or vinylene group or amethylene, ethylene, trimethylene or vinylene group having at least onesubstituent selected from the group consisting of substituents (b'),defined above; and

W represents a direct bond or a methylene, methine, ethylene or vinylenegroup.

5. Compounds of formula (I^(iv)), defined above, in which:

Y and the dotted line are as defined above;

R¹ and R² are independently selected from the group consisting ofhydrogen atoms, methyl groups and ethyl groups;

n is 1;

Z represents a methylene or ethylene group or a methylene or ethylenegroup having at least one substituent selected from the group consistingof substituents (b"), defined above; and

W represents a direct bond.

6. Compounds of formula (I^(vi)): ##STR6## in which:

Y and the dotted lines are as defined above;

R¹ and R² are independently selected from the group consisting ofhydrogen atoms and C₁ -C₄ alkyl groups;

Z represents a methylene, ethylene, trimethylene or vinylene group or amethylene, ethylene, trimethylene or vinylene group having at least onesubstituent selected from the group consisting of substituents (b'),defined above; and

W represents a direct bond or a methylene, methine, ethylene or vinylenegroup.

2. Compounds of formula (I^(vi)), defined above, in which:

Y and the dotted line are as defined above;

R¹ and R² are independently selected from the group consisting ofhydrogen atoms, methyl groups and ethyl groups;

Z represents a methylene group; and

W represents a direct bond.

8. Compounds of formula (I^(vii)): ##STR7## in which:

Y and the dotted lines are as defined above;

R¹ and R² are independently selected from the group consisting ofhydrogen atoms and C₁ -C₄ alkyl groups;

Z represents a methylene, ethylene, trimethylene or vinylene group or amethylene, ethylene, trimethylene or vinylene group having at least onesubstituent selected from the group consisting of substituents (b'),defined above; and

W represents a direct bond or a methylene, methine, ethylene or vinylenegroup. which:

Y and the dotted lines are as defined above;

R¹ and R² are independently selected from the group consisting ofhydrogen atoms, methyl groups and ethyl groups;

Z represents a methylene group; and

W represents a direct bond.

The compounds of the invention necessarily contain at least one carboxygroup in the group of formula --W--COOH, which may be at any of the 2, 5and 6 positions. Where substituent (a) also represents a carboxy group,then the compounds may contain one or more additional carboxy groups.Such carboxy groups may, independently of each other, form esters,amides and salts and, where such esters, amides or salts are formed andwhere there are two or more carboxy groups in the compound, the groupsmay be the same or different.

Where the carboxy group is esterified, the nature of the resulting esteris not critical to the present invention. In principle, the compounds ofthe invention, being carboxylic acids, will form esters with anyester-forming alcohol and all such esters form part of the presentinvention. However, where the esters are to be employed for therapeuticpurposes, it is, of course, necessary that the resulting esters shouldbe pharmaceutically acceptable, which, as is understood in the art,means that the esters should not have reduced activity (or unacceptablyreduced activity) and should not have increased toxicity (orunacceptably increased toxicity) as compared with the free acid.However, where the ester is to be employed for other purposes, forexample as an intermediate in the preparation of other compounds, eventhis criterion does not apply.

Examples of such esters include: C₁ -C₆, more preferably C₁ -C₄, alkylesters, for example the methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, t-butyl, pentyl and hexyl esters; aralkyl anddiarylalkyl esters, such as the benzyl, p-nitrobenzyl and benzhydrylesters; alkoxycarbonylalkyl esters, in which the alkoxy and alkyl partsare both C₁ -C₄, especially alkoxycarbonylmethyl esters, such as theethoxycarbonylmethyl and t-butoxycarbonylmethyl esters;alkoxycarbonyloxyalkyl esters in which the alkoxy and alkyl parts areboth C₁ -C₄, especially 2-(alkoxycarbonyloxy)ethyl esters, such as the2-methoxycarbonyloxyethyl, 2-ethoxycarbonyloxyethyl and2-t-butoxycarbonyloxyethyl esters; and other specific esters, such asthe phthalidyl, substituted phthalidyl, phenacyl, substituted phenacyl(e.g. p-nitrophenacyl) and (5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesters.

Likewise, where one or more of the carboxy groups has formed an amide,the precise nature of the amide is not critical, provided that, wherethe amide is to be used for therapeutic purposes, the resulting amide ispharmaceutically acceptable. Accordingly, one or more of these carboxygroups can be replaced by a carbamoyl group or a substituted carbamoylgroup, preferably an alkylcarbamoyl or dialkylcarbamoyl group in whichthe or each alkyl group is a C₁ -C₄ alkyl group (e.g. as defined abovein relation to R¹ and R²), for example a methylcarbamoyl,ethylcarbamoyl, dimethylcarbamoyl or diethylcarbamoyl group.

One more of these carboxy groups may also form salts with appropriatebases. Additionally, since the imidazolyl and pyridyl nitrogen atoms (inthe group represented by Y) are basic in character, the compounds of theinvention also form acid addition salts. The nature of such salts islikewise not critical, provided that, where they are to be used fortherapeutic purposes, the salts are pharmaceutically acceptable. A widerange of acids can form acid addition salts with the compounds of theinvention and examples of such acids include: mineral acids, such ashydrochloric acid, hydrobromic acid, nitric acid and phosphoric acid;organic carboxylic acids, such as acetic acid, trifluoroacetic acid,asparaginic acid, glutamic acid, oxalic acid, tartaric acid, citricacid, maleic acid, fumaric acid, lactic acid, salicyclic acid, malonicacid and succinic acid; and organic sulfonic acids, such asmethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.

Examples of slats with bases include: salts with metals, especiallyalkali metals and alkaline earth metals, such as the lithium, sodium,potassium, calcium and magnesium salts; the ammonium salts; salts withorganic amines, such as cyclohexylamine, diisopropylamine ortriethylamine; and salts with basic amino acids, such as lysine orarginine.

The compounds of the invention may contain several asymmetric carbonatoms and, accordingly, optical isomers of the compounds are possible.Although the various optical isomers are all represented herein by asingle formula, the present invention embraces both the individualisolated isomers and mixtures thereof.

Examples of specific compounds of the invention are given in thefollowing formulae (I-1) to (I-8), in which the substituents are asdefined in the corresponding one of Tables 1 and to 8 [i.e. Table 1relates to formula (I-1), Table 2 relates to formula (I-2) and so on].The compounds of the invention are hereinafter, where appropriate,identified by the numbers appended to them in these Tables, In thetables, the following abbreviations are used:

    ______________________________________                                               Bz          benzyl                                                            Et          ethyl                                                              -cHx       cyclohexyl                                                        Imid        1-imidazolyl                                                      Me          methyl                                                            Np          1-naphthyl                                                        Pen         1-propenyl                                                        Ph          phenyl                                                            Pr          propyl                                                             .sub.- iPr isopropyl                                                         Pyr         3-pyridyl                                                         Sty         styryl                                                            Vin         vinyl                                                      ______________________________________                                         ##STR8##

                  TABLE 1                                                         ______________________________________                                        No.  Y--Z            R.sup.1                                                                              R.sup.2                                                                             W                                           ______________________________________                                        1-1  ImidMe          H      H     Direct bond                                 1-2  ImidMe          H      H     --CH.sub.2 --                               1-3  ImidMe          H      H     ═CH--                                   1-4  ImidMe          H      H     --CH.sub.2 --CH.sub.2 --                    1-5  ImidMe          H      H     --CH═CH--                               1-6  ImidMe          Me     H     Direct Bond                                 1-7  ImidMe          Me     H     --CH.sub.2 --                               1-8  ImidMe          Me     H     ═CH--                                   1-9  ImidMe          Me     H     --CH.sub.2 --CH.sub.2 --                    1-10 ImidMe          Me     H     --CH═CH--                               1-11 ImidMe          H      4-Me  Direct bond                                 1-12 ImidMe          H      4-Me  --CH.sub.2 --                               1-13 ImidMe          H      4-Me  ═CH--                                   1-14 ImidMe          H      4-Me  --CH═CH--                               1-15 ImidMe          H      4-Me  --CH.sub.2 --CH.sub.2 --                    1-16 ImidMe          CH.sub.3                                                                             4-Me  Direct bond                                 1-17 1-ImidEt        H      H     Direct bond                                 1-18 1-ImidEt        H      H     --CH.sub.2 --                               1-19 1-ImidEt        H      H     ═CH--                                   1-20 1-ImidPr        H      H     Direct bond                                 1-21 α-ImidBz  H      H     Direct bond                                 1-22 2,4-diCl-α-ImidBz                                                                       H      H     Direct bond                                 1-23 2-F-α-ImidBz                                                                            H      H     Direct bond                                 1-24 2-MeO-α-ImidBz                                                                          H      H     Direct bond                                 1-25 2,4-diMeO-α-ImidBz                                                                      H      H     Direct bond                                 1-26 2,4,6-triMeO-α-ImidBz                                                                   H      H     Direct bond                                 1-27 2-Me-α-ImidBz                                                                           H      H     Direct bond                                 1-28 2-MeO-4-Me-α-ImidBz                                                                     H      H     Direct bond                                 1-29 2,4,6-triMe-α-ImidBz                                                                    H      H     Direct bond                                 1-30 Np-CH(Imid)-    H      H     Direct bond                                 1-31 4-F-α-ImidBz                                                                            H      H     Direct bond                                 1-32 4-MeO-α-ImidBz                                                                          H      H     Direct bond                                 1-33 2-Me-1-ImidPr   H      H     Direct bond                                 1-34 2,2-diMe-1-ImidPr                                                                             H      H     Direct bond                                 1-35 Imid-CH( -cHx)- H      H     Direct bond                                 1-36 2-ImidEt        H      H     Direct bond                                 1-37 2-ImidEt        H      H     --CH.sub.2 --                               1-38 2-ImidEt        H      H     ═CH--                                   1-39 1-Me-2-ImidEt   H      H     Direct bond                                 1-40 2-ImidPr        H      H     Direct bond                                 1-41 1- .sub.- iPr-2-ImidEt                                                                        H      H     Direct bond                                 1-42 2- .sub.- iPr-2-ImidEt                                                                        H      H     Direct bond                                 1-43 1-Ph-2-ImidEt   H      H     Direct bond                                 1-44 2-Ph-2-ImidEt   H      H     Direct bond                                 1-45 2-ImidVin       H      H     Direct bond                                 1-46 2-ImidPen       H      H     Direct bond                                 1-47 1-Me-2-ImidVin  H      H     Direct bond                                 1-48 β-ImidSty  H      H     Direct bond                                 1-49 1-Ph-2-ImidVin  H      H     Direct bond                                 1-50 PyrMe           H      H     Direct bond                                 1-51 PyrMe           H      H     --CH.sub.2--                                1-52 PyrMe           H      H     ═CH--                                   1-53 PyrMe           H      H     --CH.sub.2 --CH.sub.2 --                    1-54 PyrMe           H      H     --CH═CH--                               1-55 PyrMe           H      H     --CH.sub.2 --CH(Me)--                       1-56 PyrMe           H      H     --CH═C(Me)--                            1-57 PyrMe           CH.sub.3                                                                             H     Direct bond                                 1-58 PyrMe           CH.sub.3                                                                             H     --CH.sub.2 --                               1-59 PyrMe           CH.sub.3                                                                             H     ═CH--                                   1-60 PyrMe           CH.sub.3                                                                             H     --CH═CH--                               1-61 PyrMe           H      5-CH.sub.3                                                                          Direct bond                                 1-62 PyrMe           CH.sub.3                                                                             5-CH.sub.3                                                                          Direct bond                                 1-63 1-PyrEt         H      H     Direct bond                                 1-64 α-PyrBz   H      H     Direct bond                                 1-65 α-PyrBz   H      H     --CH.sub.2 --                               1-66 α-PyrBz   H      H     ═CH--                                   1-67 2-PyrEt         H      H     Direct bond                                 1-68 1-Me-2-PyrEt    H      H     Direct bond                                 1-69 2-PyrPr         H      H     Direct bond                                 1-70 1-Ph-2-PyrEt    H      H     Direct bond                                 1-71 2-Ph-2-PyrEt    H      H     Direct bond                                 1-72 2-PyrVin        H      H     Direct bond                                 1-73 1-Me-2-PyrVin   H      H     Direct bond                                 1-74 2-PyrPen        H      H     Direct bond                                 1-75 1-Ph-2-PyrVin   H      H     Direct bond                                 1-76 β-PyrSty   H      H     Direct bond                                 ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        No.  Y--Z          R.sup.1                                                                              R.sup.2                                                                             W                                             ______________________________________                                        2-1  ImidMe        H      H     Direct bond                                   2-2  ImidMe        H      H     --CH.sub.2 --                                 2-3  ImidMe        H      H     --CH.sub.2 --CH.sub.2 --                      2-4  ImidMe        H      H     --CH═CH--                                 2-5  ImidMe        CH.sub.3                                                                             H     Direct bond                                   2-6  ImidMe        CH.sub.3                                                                             H     --CH.sub.2 --                                 2-7  ImidMe        CH.sub.3                                                                             H     --CH.sub.2 --CH.sub.2 --                      2-8  ImidMe        CH.sub.3                                                                             H     --CH═CH--                                 2-9  ImidMe        H      4-CH.sub.3                                                                          Direct bond                                   2-10 ImidMe        H      4-CH.sub.3                                                                          --CH.sub.2 --                                 2-11 ImidMe        H      4-CH.sub.3                                                                          --CH═CH--                                 2-12 ImidMe        H      4-CH.sub.3                                                                          --CH.sub.2 --CH.sub.2 --                      2-13 ImidMe        CH.sub.3                                                                             4-CH.sub.3                                                                          Direct bond                                   2-14 1-ImidEt      H      H     Direct bond                                   2-15 1-ImidEt      H      H     --CH.sub.2 --                                 2-16 1-ImidPr      H      H     Direct bond                                   2-17 α-ImidBz                                                                              H      H     Direct bond                                   2-18 2,4-diCl-α-                                                                           H      H     Direct bond                                        ImidBz                                                                   2-19 2-F-α-ImidBz                                                                          H      H     Direct bond                                   2-20 2-MeO-α-                                                                              H      H     Direct bond                                        ImidBz                                                                   2-21 2,4-diMeO-α-                                                                          H      H     Direct bond                                        ImidBz                                                                   2-22 2,4,6-triMeO- H      H     Direct bond                                        α-ImidBz                                                           2-23 2-Me-α-ImidBz                                                                         H      H     Direct bond                                   2-24 2-MeO-4-Me-α-                                                                         H      H     Direct bond                                        ImidBz                                                                   2-25 2,4,6-triMe-α-                                                                        H      H     Direct bond                                        ImidBz                                                                   2-26 Np-CH(Imid)-  H      H     Direct bond                                   2-27 4-F-α-ImidBz                                                                          H      H     Direct bond                                   2-28 4-MeO-α-ImidBz                                                                        H      H     Direct bond                                   2-29 2-Me-1-ImidPr H      H     Direct bond                                   2-30 2,2-diMe-1-ImidPr                                                                           H      H     Direct bond                                   2-31 Imid-CH( -cHx)-                                                                             H      H     Direct bond                                   2-32 2-ImidEt      H      H     Direct bond                                   2-33 2-ImidEt      H      H     --CH.sub.2 --                                 2-34 1-Me-2-ImidEt H      H     Direct bond                                   2-35 2-ImidPr      H      H     Direct bond                                   2-36 1- .sub.- iPr-2-ImidEt                                                                      H      H     Direct bond                                   2-37 2- .sub.- iPr-2-ImidEt                                                                      H      H     Direct bond                                   2-38 1-Ph-2-ImidEt H      H     Direct bond                                   2-39 2-Ph-2-ImidEt H      H     Direct bond                                   2-40 2-ImidVin     H      H     Direct bond                                   2-41 2-ImidPen     H      H     Direct bond                                   2-42 1-Me-2-ImidVin                                                                              H      H     Direct bond                                   2-43 β-ImidSty                                                                              H      H     Direct bond                                   2-44 1-Ph-2-ImidVin                                                                              H      H     Direct bond                                   2-45 PyrMe         H      H     Direct bond                                   2-46 PyrMe         H      H     --CH.sub.2 --                                 2-47 PyrMe         H      H     --CH.sub.2 --CH.sub.2 --                      2-48 PyrMe         H      H     --CH═CH--                                 2-49 PyrMe         H      H     --CH.sub.2 --CH(Me)--                         2-50 PyrMe         H      H     --CH═CMe--                                2-51 PyrMe         CH.sub.3                                                                             H     Direct bond                                   2-52 PyrMe         CH.sub.3                                                                             H     --CH.sub.2 --                                 2-53 PyrMe         CH.sub.3                                                                             H     --CH═CH--                                 2-54 PyrMe         H      5-CH.sub.3                                                                          Direct bond                                   2-55 PyrMe         CH.sub.3                                                                             5-CH.sub.3                                                                          Direct bond                                   2-56 1-PyrEt       H      H     Direct bond                                   2-57 α-PyrBz H      H     Direct bond                                   2-58 α-PyrBz H      H     --CH.sub.2 --                                 2-59 2-PyrEt       H      H     Direct bond                                   2-60 1-Me-2-PyrEt  H      H     Direct bond                                   2-61 2-PyrPr       H      H     Direct bond                                   2-62 1-Ph-2-PyrEt  H      H     Direct bond                                   2-63 2-Ph-2-PyrEt  H      H     Direct bond                                   2-64 2-PyrVin      H      H     Direct bond                                   2-65 1-Me-2-PyrVin H      H     Direct bond                                   2-66 2-PyrPen      H      H     Direct bond                                   2-67 1-Ph-2-PyrVin H      H     Direct bond                                   2-68 β-PyrSty H      H     Direct bond                                   ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                        No.   Y--Z          R.sup.1 R.sup.2                                                                              W                                          ______________________________________                                        3-1   ImidMe        H       H      Direct bond                                3-2   ImidMe        H       H      --CH.sub.2 --                              3-3   ImidMe        CH.sub.3                                                                              H      Direct bond                                3-4   ImidMe        CH.sub.3                                                                              H      --CH.sub.2 --                              3-5   ImidMe        H       4-CH.sub.3                                                                           Direct bond                                3-6   ImidMe        H       4-CH.sub.3                                                                           --CH.sub.2 --                              3-7   ImidMe        CH.sub.3                                                                              4-CH.sub.3                                                                           Direct bond                                3-8   1-ImidEt      H       H      Direct bond                                3-9   α-ImidBz                                                                              H       H      Direct bond                                3-10  2-MeO-α-                                                                              H       H      Direct bond                                      ImidBz                                                                  3-11  2,4,6-triMe-α-                                                                        H       H      Direct bond                                      ImidBz                                                                  3-12  4-F-α-ImidBz                                                                          H       H      Direct bond                                3-13  4-MeO-α-ImidBz                                                                        H       H      Direct bond                                3-14  2-ImidEt      H       H      Direct bond                                3-15  2-Ph-2-ImidEt H       H      Direct bond                                3-16  PyrMe         H       H      Direct bond                                3-17  PyrMe         H       H      --CH.sub.2 --                              3-18  PyrMe         CH.sub.3                                                                              H      Direct bond                                3-19  PyrMe         CH.sub.3                                                                              H      --CH.sub.2 --                              3-20  2-PyrEt       H       H      Direct bond                                ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        No.   Y--Z          R.sup.1 R.sup.2                                                                              W                                          ______________________________________                                        4-1   ImidMe        H       H      Direct bond                                4-2   ImidMe        H       H      --CH.sub.2 --                              4-3   ImidMe        CH.sub.3                                                                              H      Direct bond                                4-4   α-ImidBz                                                                              H       H      Direct bond                                4-5   2-MeO-α-ImidBz                                                                        H       H      Direct bond                                4-6   2,4,6-triMe-α-                                                                        H       H      Direct bond                                      ImidBz                                                                  4-7   4-F-α-ImidBz                                                                          H       H      Direct bond                                4-8   4-MeO-α-ImidBz                                                                        H       H      Direct bond                                4-9   2-ImidEt      H       H      Direct bond                                4-10  2-Ph-2-ImidEt H       H      Direct bond                                4-11  PyrMe         H       H      Direct bond                                4-12  PyrMe         H       H      --CH.sub.2 --                              4-13  PyrMe         CH.sub.3                                                                              H      Direct bond                                4-14  PyrMe         CH.sub.3                                                                              H      --CH.sub.2 --                              ______________________________________                                    

                  TABLE 5                                                         ______________________________________                                        No.   Y--Z          R.sup.1 R.sup.2                                                                              W                                          ______________________________________                                        5-1   ImidMe        H       H      Direct bond                                5-2   ImidMe        H       H      --CH.sub.2 --                              5-3   ImidMe        CH.sub.3                                                                              H      Direct bond                                5-4   ImidMe        CH.sub.3                                                                              4-CH.sub.3                                                                           Direct bond                                5-5   α-ImidBz                                                                              H       H      Direct bond                                5-6   2-MeO-α-ImidBz                                                                        H       H      Direct bond                                5-7   2-ImidEt      H       H      Direct bond                                5-8   2-ImidVin     H       H      Direct bond                                5-9   PyrMe         H       H      Direct bond                                5-10  PyrMe         CH.sub.3                                                                              H      Direct bond                                5-11  PyrMe         CH.sub.3                                                                              H      --CH.sub.2 --                              5-12  2-PyrEt       H       H      Direct bond                                ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                        No.   Y--Z          R.sup.1 R.sup.2                                                                              W                                          ______________________________________                                        6-1   ImidMe        H       H      Direct bond                                6-2   ImidMe        H       H      --CH.sub.2 --                              6-3   ImidMe        CH.sub.3                                                                              H      Direct bond                                6-4   α-ImidBz                                                                              H       H      Direct bond                                6-5   2-MeO-α-ImidBz                                                                        H       H      Direct bond                                6-6   2-ImidEt      H       H      Direct bond                                6-7   2-Ph-2-ImidEt H       H      Direct bond                                6-8   2-ImidVin     H       H      Direct bond                                6-9   PyrMe         H       H      Direct bond                                6-10  PyrMe         CH.sub.3                                                                              H      Direct bond                                6-11  PyrMe         CH.sub.3                                                                              H      --CH.sub.2 --                              6-12  2-PyrEt       H       H      Direct bond                                ______________________________________                                    

                  TABLE 7                                                         ______________________________________                                        No.   Y--Z          R.sup.1 R.sup.2                                                                              W                                          ______________________________________                                        7-1   ImidMe        H       H      Direct bond                                7-2   ImidMe        H       H      --CH.sub.2 --                              7-3   ImidMe        CH.sub.3                                                                              H      Direct bond                                7-4   ImidMe        H       6-CH.sub.3                                                                           Direct bond                                7-5   ImidMe        H       6-CH.sub.3                                                                           --CH.sub.2 --                              7-6   α-ImidBz                                                                              H       H      Direct bond                                7-7   2-MeO-α-ImidBz                                                                        H       H      Direct bond                                7-8   2-ImidEt      H       H      Direct bond                                7-9   PyrMe         H       H      Direct bond                                7-10  PyrMe         H       H      --CH.sub.2 --                              7-11  PyrMe         CH.sub.3                                                                              H      Direct bond                                7-12  α-PyrBz H       H      Direct bond                                ______________________________________                                    

                  TABLE 8                                                         ______________________________________                                        No.     Y--Z          R.sup.1 R.sup.2                                                                            W                                          ______________________________________                                        8-1     ImidMe        H       H    Direct bond                                8-2     ImidMe        H       H    --CH.sub.2 --                              8-3     ImidMe        CH.sub.3                                                                              H    Direct bond                                8-4     2-MeO-α-ImidBz                                                                        H       H    Direct bond                                8-5     2-ImidEt      H       H    Direct bond                                8-6     PyrMe         H       H    Direct bond                                8-7     PyrMe         CH.sub.3                                                                              H    Direct bond                                8-8     α-PyrBz H       H    Direct bond                                8-9     α-PyrBz H       H    --CH.sub.2 --                              ______________________________________                                    

Of the above Compounds, preferred compounds are Compounds No. 1-1, 1-2,1-6, 1-16, 1-17, 1-21, 1-24, 1-27, 1-29, 1-36, 1-44, 1-45, 1-50, 1-57,1-58, 1-62, 1-67, 2-1, 2-5, 2-6, 2-13, 2-17, 2-18, 2-19, 2-20, 2-23,2-32, 2-39, 2-45, 2-51, 2-52, 3-1, 3-3, 3-14, 3-16, 3-18, 3-20, 4-1,4-4, 4-9, 4-11, 5-1, 5-4, 5-7, 5-9, 5-10, 6-1, 6-3, 6-6, 6-9, 7-1, 7-8,7-9, 8-1, 8-5 and 8-6. Of these, more preferred compounds are CompoundsN. 1-1, 1-6, 1-36, 1-50, 1-57, 1-67, 2-1, 2-5, 2-17, 2-32, 2-45, 3-1,3-16, 4-1, 4-4, 4-9 and 5-1 and the most preferred compounds areCompounds No. 1-1 and 2-1, i.e.:

1-1. 4,5,6,7-tetrahydro-2-(1-imidazolyl)methylthianaphthene-6-carboxylicacid

2-1. 4,5-dihydro-2-(1-imidazolyl)methylthianaphthene-6-carboxylic acid

Also preferred are pharmaceutically acceptable salts, esters and amides,particularly salts and esters of the above compounds, notably the alkalimetal (especially sodium) salts and lower alkyl (especially methyl)esters.

In general terms, the compounds of the present invention may be preparedby reacting a compound of formula (II): ##STR9## (in which R¹, R², n andthe broken lines are as defined above; one of B¹ and B² represents thegroup of formula --W--COOH represented by A¹ or A² or such a group inwhich the carboxy group is protected; and the other of B¹ and B²represents an active group) with an imidazolyl or pyridyl compound tointroduce the imidazolyl or pyridyl group represented by Y into saidcompound and, if necessary, subjecting the resulting compound toreduction and/or hydrolysis and/or deprotection.

In more detail, the compounds of the invention may be prepared asdescribed in relation to any of the following Methods A--F.

Method A

In this method, a compound of formula (Ia): ##STR10## [in which R¹, R²,W, n and the broken lines are as defined above: Y¹ represents animidazolyl group; and Z¹ represents methylene, ethylene or trimethylenegroup which is unsubstituted or has at least one substituent selectedfrom the group consisting of substituents (b), defined above; said groupof formula --Z¹ --Y¹ being at any one of the 2-, 5- and 6- positions ofthe thianaphthene system and said group of formula --W--COOH being atany one of said 2-, 5- and 6- positions not occupied by said group offormula --Z¹ --Y¹ ], that is to say a compound of formula (Ia1);##STR11## a compound of formula (Ia2): ##STR12## or a compound offormula (Ia3): ##STR13## (in which R¹, R², n, W, Y¹, Z¹ and the brokenand dotted lines are as defined above), may be produced by reacting acompound of formula (III): ##STR14## (in which R¹, R², W, n, Z¹ and thebroken lines are as defined above; R³ presents a carboxy-protectinggroup; and X represents a halogen atom, a lower alkanesulfonyloxy groupor an arylsulfonyloxy group; said group of formula --Z¹ --X being at anyone of the 2-, 5- and 6- positions of the thianaphthene system and saidgroup of formula --W--COOR³ being at any one of said 2-, 5- and 6-positions not occupied by said group of formula --Z¹ --X) with acompound of formula (IV):

    Y.sup.1 H                                                  (IV)

(in which Y¹ is as defined above), i.e., imidazole, or with an alkalimetal (e.g. lithium, sodium or potassium) salt thereof and, ifnecessary, hydrolizing the resulting compound.

In the above formulae (II), (Ia) and (IIII), the provisions relating toA² in the compounds of formula (I) apply, mutatis mutandis, to thecorresponding group B², --Z¹ --Y¹, --W--COOH, --Z¹ --X or --W--COOR³,i.e. when it is at the 5-position, there should be a single bond betweenthe 6- and 7- positions, and, when it is at the 6-position, there shouldbe a single bond between the 4- and 5- positions. The same applies inthe respective formulae given hereafter.

Where X represents a halogen atom, there is preferably a chlorine,bromine or iodine atom. Where X represents a lower alkanesulfonyloxygroup, this is preferably a C₁ -C₄ alkanesulfonyloxy group, for examplea methanesulfonyloxy or ethanesulfonyloxy group. Where X represents anarylsulfonyloxy group, the aryl part may be as defined in relation tothe substituted or unsubstituted aryl groups represented by R¹ and R²,and preferred such arylsulfonyloxy groups include the benzenesulfonyloxyand p-toluenesulfonyloxy groups.

Where the carboxy group in the group of formula --W--COOH is protected,it is preferably protected by conversion to an ester group, particularlya lower alkyl ester, and R³ is for example a methyl, ethyl, propyl,isopropyl, butyl, isobutyl or t-butyl group.

The reaction between the compound of formula (III) and the compound offormula (IV) is preferably effected in the presence of a solvent, thenature of which is not critical, provided that it has no adverse effectupon the reaction. Examples of suitable solvents include: halogenatedhydrocarbons, particularly halogenated aliphatic hydrocarbons, such asmethylene chloride, chloroform or carbon tetrachloride; alcohols, suchas methanol, ethanol or t-butanol; aromatic hydrocarbons, such asbenzene, toluene or xylene; nitriles, such as acetonitrile; and loweraliphatic acid amides, such as dimethylformamide.

The reaction will take place over a wide range of temperatures and theparticular temperature chosen is not critical to the invention. However,we generally find it convenient to carry out the reaction at atemperature in the range from 10° C. to the boiling point of the solventemployed. The time required for the reaction will vary, depending uponmany factors, notably the nature of the reagents and the reactiontemperature; however, within the range of temperatures indicated above,a period of form 1 to 20 hours will normally suffice.

Where the resulting compound is to be hydrolized, this may be effectedby conventional means by contacting the ester obtained in the abovereaction with a hydrolizing agent, which may be an acid or a base. Thereis no particular restriction upon the nature of the acid or base to beemployed as hydrolizing agent, and any such compound commonly used forhydrolysis may equally be used in the present reaction. However,examples of suitable hydrolizing agents include: mineral acids, such ashydrochloric acid, hydrobromic acid and sulfuric acid; and alkali metalhydroxides, such as sodium hydroxide or potassium hydroxide.

The reaction is normally carried out in the presence of a solvent, thenature of which is not critical, provided that it has no adverse effectupon the reaction. Generally, we prefer to use as solvent an alcohol,such as methanol or ethanol, or a mixture of such an alcohol and water.

The reaction will take place over a wide range of temperatures and thereis no particular limitation on the precise temperature employed. Wegenerally find it convenient to carry out the reaction at a temperaturewithin the range from room temperature to 110° C. The time required forthe reaction may vary widely, depending upon many factors, notably thereaction temperature and the nature of the hydrolizing agent used.However, at temperatures within the range suggested above, a period offrom 10 minutes to 6 hours will normally suffice.

After completion of the reaction, the desired product may be recoveredfrom the reaction mixture by conventional recovery techniques and then,if required, it may be further purified by such conventional techniquesas recrystallization, distillation or the various chromatographytechniques, notably column chromatography.

Method B

Thianaphthene compounds of formula (Ia), defined in Method A above, mayalso be produced by reacting a compound of formula (V): ##STR15## (inwhich R¹, R², R³, W, Z¹, n and the broken lines are as defined above;said group of formula --Z¹ --OH being at any one of the 2-, 5- and 6-positions of the thianaphthene system and said group of formula--W--COOR³ being at any one of said 2-, 5- and 6- positions not occupiedby said group of formula --Z¹ --OH) with a thionyldiimidazole compoundof formula (VI):

    Y.sup.1 --S(═O)--Y.sup.1                               (VI)

(in which Y¹ is as defined above) and, if necessary, hydrolizing theresulting compound.

As explained in Method A, the provisos relating to A¹ apply mutatismutandis to whichever of said groups --Z¹ --OH and --W--COOR² occupiesthe 5- or 6- position.

The reaction of the compound of formula (V) with the thionyldiimidazolecompounds of formula (VI) is preferably effected in the presence of asolvent, the nature of which is not critical, provided that it has noadverse effect upon the reaction. Examples of suitable solvents include:halogenated hydrocarbons, particularly halogenated aliphatichydrocarbons, such as methylene chloride or chloroform; ethers, such asdiethyl ether, tetrahydrofuran or dioxane; and aromatic hydrocarbons,such as benzene, toluene or xylene. Although not essential, the reactionis facilitated by carrying it out in the presence of a base, preferablyan organic base and more preferably a tertiary amine, such as4-dimethylaminopyridine.

The reaction will take place over a wide range of temperatures and thereis no particular limitation on the precise temperature chosen. Wegenerally find it convenient to carry out the reaction at a temperaturewithin the range from 0° C. to the boiling point of the solventemployed. The time required for the reaction may vary widely, dependingupon many factors, notably the nature of the reagents and the reactiontemperature. However, at a temperature within the range suggested above,a period of from 1 minute to 12 hours will normally suffice.

After completion of the reaction, the reaction mixture is preferablypoured into water and then treated by conventional means to recover thedesired compound. If necessary, this may be further purified byconventional means, for example recrystallization, distillation of thevarious chromatography techniques, notably column chromatography.

If hydrolysis is required, this may be carried out before or afterrecovery and/or purification by the conventional method described inMethod A.

Method C

Compounds of formula (Ic): ##STR16## (in which R¹, R², W, Z, n and thebroken lines are as defined above; and Y² represents a pyridyl group;said group of formula --Z--Y² being at any one of the 2-, 5- and 6-positions of the thianaphthene system and said group of formula--W--COOH being at any one of said 2- 5- and 6- positions not occupiedby said group of formula --Z--Y²) can be produced by reacting a compoundof formula (VII): ##STR17## [in which R¹, R², R³ W, n and the brokenlines are as defined above; R⁴ represents a hydrogen atom or any of thegroups defined as substituents (b), i.e. a C₁ -C₄ alkyl group, a C₃ -C₆cycloalkyl group, a C₆ --C₁₀ aryl group, a substituted C₆ -C₁₀ arylgroup having at least one of substituents (a) or a heterocyclic group;and m represents the cypher 0 or the integer 1 or 2; said group offormula --(CH₂)_(m) --C(═O)--R⁴ being at any one of the 2-, 5- and 6-positions of the thianaphthene system and said group of formula--W--COOR³ being at any one of said 2-, 5- and 6- positions not occupiedby said group of formula --(CH₂)_(m) -C(═O)--R⁴ ] with a lithiumcompound of formula (VIII):

    Y.sup.2 --Li                                               (VIII)

(in which Y² is as defined above), reducing or dehydrating the resultingcompound and then, if desired, hydrolizing the product thus obtained.

The first step of this reaction, i.e. the reaction of the compound offormula (VII) with the lithium compound of formula (VIII) converts thegroup of formula --(CH₂)_(m) --C(═O)--R⁴ in the compound of formula(VII) to a group of formula: ##STR18## (in which m, Y² and R⁴ are asdefined above). This reaction is preferably effected in the presence ofa solvent, the nature of which is not critical, provided that it has noadverse effect upon the reaction. Suitable solvents include ethers,particularly diethyl ether or tetrahydrofuran. The reaction will takeplace over a wide range of temperatures and the precise temperaturechosen is not particularly critical, although we generally find itconvenient to carry out the reaction at a temperature of form -73° C. to+30° C. The time required for the reaction may vary widely, dependingupon many factors, notably the reaction temperature and the nature ofthe reagents; however, at a temperature within the suggested range, aperiod of from 30 minutes to 5 hours will normally suffice.

After completion of the reaction, the excess lithium compound (VIII) isdecomposed, e.g. by adding water or, more preferably, an aqueoussolution of a salt, especially an ammonium salt such as ammoniumchloride. The reaction mixture is then preferably treated byconventional means to recover the desired compound containing theaforementioned group of formula (B) and then the resulting compound may,if required, be further purified by such conventional means asrecrystallization, distillation of the various chromatographytechniques, notably column chromatography.

In the next step of the reaction, the compound containing the group offormula (B) defined above is reduced. The reaction is preferablyeffected by means of hydrogen in the presence of a catalyst, such aspalladium-on-carbon or platinum oxide. The reaction is preferablyeffected in the presence of a mineral acid, such as hydrochloric acid,hydrobromic acid or sulfuric acid. The reaction is also preferablyeffected in the presence of a solvent, the nature of which is notcritical, provided that it has no adverse effect upon the reaction.Examples of suitable solvents include: esters, such as ethyl acetate;aromatic hydrocarbons, such as benzene or toluene; and alcohols, such asmethanol or ethanol. After completion of the reaction, the resultingproduct may be recovered from the reaction mixture of conventionalmeans, to give a compound of formula (Ic) in which Z represents amethylene, ethylene or trimethylene group which is unsubstituted or hasone or more of substituents (b).

Where m represents the integer 1, the resulting compound can bedehydrated to give a compound of formula (Ic) in which Z represents avinylene group. This reaction is preferably effected in the presence ofan organic solvent, the nature of which is not critical, provided thatit has no adverse effect upon the reaction. Examples of suitable organicsolvents include: aromatic hydrocarbons, such as benzene, toluene orxylene; and ethers, such as dioxane or tetrahydrofuran. The dehydrationreaction is preferably effected by the addition of a catalytic amount ofa strong acid, for example an organic sulfonic acid such asp-toluenesulfonic acid or a mineral acid such as hydrochloric acid,hydrobromic acid or sulfuric acid. The water produced in the reaction isremoved, preferably in the course of the reaction, to assist thereaction to go to completion, and preferably by azeotropic distillationwith heating.

If necessary, the product is then subjected to hydrolysis as describedin Method A. After completion of the reaction, the desired product maybe recovered from the reaction mixture by conventional means, to givefrom the reaction mixture by conventional means, to give a compound offormula (Ic) in which Z represents a vinylene group, which may beunsubstituted or have at least one of substituents (b).

If required, the resulting compound prepared as described above may befurther purified by such conventional techniques as recrystallization orthe various chromatography techniques, notably column chromatography.

Method D

Compounds of formula (Id): ##STR19## [in which R¹, R², W, Y¹, n and thebroken lines are as defined above; and Z² presents a vinylene group or avinylene group having at least one of substituents (b) defined above,that is to say an alkyl group, a cycloalkyl group, a substituted orunsubstituted aryl group or a heterocyclic group; said group of formula--Z² --Y¹ being at any one of the 2-, 5- and 6- positions of thethianaphthene system and said group of formula --W--COOH being at anyone of said 2-, 5- and 6- positions not occupied by said group offormula --Z² --Y¹ ] can be prepared by reacting a compound of formula(VIII): ##STR20## [in which R¹, R², R³, R⁴, W, n and the broken linesare as defined above; said group of formula --CH₂ --C(═O)--R⁴ being atany one of the 2-, 5- and 6- positions of the thianaphthene system andsaid group of formula --W--COOR³ being at any one of said 2-, 5- and 6-positions not occupied by said group of formula --CH₂ --C(═O)--R⁴ ],i.e. a compound of formula (VII) (see Method C) in which m is 1, with athionyldiimidazole compound of formula (VI):

    Y.sup.1 --S(═O)--Y.sup.1                               (VI)

(in which Y¹ is as defined above--see Method B) and, if necessary,hydrolizing the resulting compound.

The reaction of these compounds may be carried out employing the samereaction conditions and subsequent treatment as described in Method B.

Method E

A thianaphthene derivative of formula (Ie): ##STR21## [in which R¹, R²,W, Y¹, n and the broken lines are as defined above; and Z³ represents anethylene, trimethylene or vinylene group or such a group having at leastone substituent selected from the group consisting of substituents (b),that is to say the alkyl, cycloalkyl, substituted and unsubstituted aryland heterocyclic groups defined above; said group of formula --Z³ --Y¹being at any one of the 2-, 5- and 6- positions of the thianaphthenesystem and said group of formula --W--COOH being at any one of said 2-,5- and 6- positions not occupied by said group of formula --Z³ --Y¹ ]can be prepared by reacting a compound of formula (IX): ##STR22## [inwhich R¹, R², R³, Y¹, W, n and the broken lines are as defined above;and p is 1 or 2; said group of formula --C(═O)--(CH₂)_(p) --Y¹ being atany one of the 2-, 5- and 6- positions of the thianaphthene system andsaid group of formula --W--COOR³ being at any one of said 2-, 5- and 6-positions not occupied by said group of formula --C(═O)--(CH₂)_(p) --Y¹] with a reducing agent or with an organolithium compound of formula(X):

    R.sup.5 Li                                                 (X)

or with a Grignard reagent of formula (XI):

    R.sup.5 MgX'                                               (XI)

[in which R⁵ represents any one of the groups defined above assubstituents (b), that is to say a C₁ -C₄ alkyl group, a C₃ -C₆cycloalkyl group, a C₆ -C₁₀ aryl group, a substituted C₆ -C₁₀ aryl groupor a heterocyclic group; and X' represents a halogen atom, for example achlorine, bromine or iodine atom] to give a compound of formula (XII);##STR23## [in which R¹, R², R³, W, Y¹, n, p and the broken lines are asdefined above; said group of formula --(OH)C(R⁴)--(CH₂)_(p) --Y¹ beingat any one of the 2-, 5- and 6- positions of the thianaphthene systemand said group of formula --W--COOR³ being at any one of said 2-, 5- and6- positions not occupied by said group of formula--(OH)C(R⁴)--(CH₂)_(p) --Y¹ ], and then reducing and/or dehydrating saidcompound of formula (XII) and, if desired, hydrolizing the resultingproduct.

Where, in the first step of this reaction, the compound of formula (IX)is reacted with a reducing agent, the reducing agent is preferably ametal hydride, such as sodium borohydride or sodium cyanoborohydride.The reaction is preferably effected in the presence of a solvent, thenature of which is not critical, provided that it has no adverse effecton the reaction. Suitable solvents include, for example: ethers, such asdiethyl ether or tetrahydrofuran; and alcohols, such as methanol. Thereaction will take place over a wide range of temperatures and theparticular temperature chosen is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature in the range from 0° C. to the boiling temperature of thesolvent employed. The time required for the reaction may vary widely,depending upon many factors, notably the nature of the reagents and thereaction temperature; however, at a temperature within the suggestedrange, a period of from 30 minutes to 5 hours will normally suffice.After completion of the reaction, the reaction mixture may be treated byconventional means to recover the desired product, after which theproduct, the compound of formula (XII), may be further purified by suchconventional techniques as recrystallization, distillation or thevarious chromatography techniques, notably column chromatography.

Alternatively, in the first step of the reaction, the compound offormula (IX) may be reacted with the organolithium compound of formula(X). This reaction is preferably effected in the presence of a solvent,the nature of which is not critical, provided that it has no adverseeffect upon the reaction. Suitable solvents include ethers, such asdiethyl ether or tetrahydrofuran. The reaction will take place over awide range of temperatures and the precise temperature chosen is notcritical to the present invention. In general, we find it convenient tocarry out the reaction at a temperature in the range from -73° C. to+30° C. The time required for the reaction may vary widely, dependingupon many factors, notably the nature of the reagents and the reactiontemperature; however, at a temperature within the suggested range, aperiod of from 30 minutes to 5 hours will normally suffice. Aftercompletion of the reaction, we prefer to decompose excess organolithiumcompound by adding water or, more preferably, an aqueous solution of asalt, especially an ammonium salt such as ammonium chloride, to thereaction mixture. After this the mixture may be treated by conventionalmeans to recover the desired compound of formula (XII) which may then,if required, be further purified by such conventional techniques asdistillation, recrystallization or the various chromatographytechniques, notably column chromatography.

As a further alternative, the compound of formula (IX) may be reactedwith a Grignard reagent of formula (XI). This reaction is preferablyeffected in the presence of a solvent, the nature of which is notcritical, provided that it has no adverse effect upon the reaction andis essentially inert to the Grignard reagent; examples of suitablesolvents include such ethers as diethyl ether and tetrahydrofuran. Thereaction will take place over a wide range of temperatures and theparticular temperature chosen is not critical to the invention. Wegenerally find it convenient to carry out the reaction at a temperaturein the range from 0° C. to the boiling temperature of the solventemployed. The time required for the reaction may vary widely, dependingupon many factors, notably the nature of the reagents and the reactiontemperature; however, at temperatures within the suggested range, aperiod of from 30 minutes to 10 hours will normally suffice. Aftercompletion of the reaction, we prefer to decompose excess Grignardreagent (XI) by adding water or, more preferably, an aqueous solution ofa salt, especially an ammonium salt such as ammonium chloride, to thereaction mixture. The mixture may then be treated by conventional meansto recover the desired compound of formula (XII), which may then, ifrequired, be further purified by such conventional techniques asdistillation, recrystallization or the various chromatographytechniques, notably column chromatography.

The resulting compound of formula (XII), however prepared, is thensubjected to reduction and/or dehydration. If desired, the compound offormula (XII) may then be subjected to the same reduction or dehydrationreactions as described in relation to Method C. However, a morepreferred sequence of reactions is as follows.

First, the compound of formula (XII) is reacted with an alkali metalhydride, for example sodium hydride, by stirring the compound with thehydride, preferably in the presence of a suitable solvent. The nature ofthe solvent is not critical, provided that it has no adverse effect uponthe reaction. Suitable solvents include: ethers, such as diethyl etheror tetrahydrofuran; and aromatic hydrocarbons, such as benzene ortoluene. The reaction temperature is not critical, and we generally findit convenient to carry out the reaction at a temperature in the range offrom 0° C. to the boiling point of the solvent employed. Subsequently,carbon disulfide and a lower alkyl halide, e.g. a methyl halide such asmethyl iodide, are added. These are then allowed to react to give acompound of formula (XIII): ##STR24## [in which R¹, R², R³, R⁴, W, Y¹,n, p and the broken lines are as defined above; and R⁶ represents alower alkly group, preferably a methyl group; each of the groups offormula --W--COOR³ and --(R⁴)C(--OCS₂ R⁶)--(CH₂)_(p) --Y¹ being at anyone of the 2-, 5- and 6- positions, provided that they are not both atthe same position]. The reaction will taken place over a wide range oftemperatures and the precise temperature chosen is not particularlycritical; however, we generally find it convenient to carry out thereaction at a temperature within the range from 0° C. to the boilingpoint of the solvent employed. The time required for the reaction mayvary widely, depending upon the nature of the reagents and the reactiontemperature; however, at a temperature in the suggested range, a periodof from 10 minutes to 1 hour will normally suffice. The reaction ispreferably effected in the same reaction medium as was used for thereaction with the alkali metal hydride.

The resulting compound is then reduced, preferably with tributyltinhydride, or dehydrated and, if necessary, hydrolized, to give thedesired compound of formula (Ie).

Free radical reduction of the compound of formula (XIII) withtributyltin hydride is preferably effected in the presence of an organicsolvent, the nature of which is not critical, provided that it does notinterfere with the reaction. Examples of suitable solvents include:ethers, such as diethyl ether or tetrahydrofuran; and aromatichydrocarbons, such as benzene or toluene; a single one o these solventsor a mixture of any two or more thereof may be employed. The reaction ispreferably also effected in the presence of α,α'-azobisisobutyronitrile.The reaction is preferably effected with heating, suitably under reflux,to give the desired compound of formula (Ie) in which Z represents anethylene or trimethylene group which is unsubstituted or has at leastone of substituents (b). The time required for the reaction may varywidely, depending upon many factors, notably the reaction temperature,but a period of from 10 to 30 hours will normally suffice.

Alternatively, the compound of formula (XIII) may be dehydrated. This ispreferably effected by the addition of a catalytic amount of a strongacid, for example an organic sulfonic acid such as p-toluenesulfonicacid or a mineral acid such as hydrochloric acid, hydrobromic acid orsulfuric acid. The reaction is preferably effected in the presence of anorganic solvent, the nature of which is not critical, provided that itdoes not interfere with the reaction. Suitable solvents include, forexample: aromatic hydrocarbons, such as benzene, toluene or xylene; andethers, such as dioxane or tetrahydrofuran. The water produced in thereaction is preferably removed in the course of the reaction to assistthe reaction to go to completion. Removal of the water is preferablyeffected by means of azeotropic distillation. The resulting product is acompound of formula (Ie) in which Z represents a vinylene group which isunsubstituted or has at least one of substituents (b).

If required, the resulting product may be subjected to hydrolysis, asdescribed in relation to Method A.

The resulting compounds may be separated from their respective reactionmixtures by conventional means and, is required, may be further purifiedby such conventional techniques as recrystallization or the variouschromatography techniques, notably column chromatography.

Method F

Tetrahydrothianaphthene derivatives of formula (If): ##STR25## (in whichR¹, R², W, Y, Z and n are as defined above; each of said groups offormula --Z--Y and --W--COOH being at any one of the 2-, 5- and 6-positions, provided that they are not both at the same position) may beprepared from the corresponding dihydrothianaphthene derivative (i.e.having a double bond between the 4- and 5- or the 6- and 7- positions)by reductive hydrogenation. The starting material may have been preparedby any of the forgoing Methods A-E.

The reduction process is preferably effected in the presence of asolvent, the nature of which is not critical, provided that it has noadverse effect upon the reaction. Examples of suitable solvents include:esters, such as ethyl acetate: aromatic hydrocarbons, such as benzene ortoluene; alcohols, such as methanol or ethanol; and ethers, such astetrahydrofuran or dioxane. The reaction takes place in the presence ofhydrogen and of a catalyst, preferably palladium-on-carbon or platinumoxide.

After completion of the reaction, the resulting product may be recoveredfrom the reaction mixture by conventional means and, if required, beforeor after recovery may be subjected to hydrolysis as described in MethodA. The product of formula (If) may then, if desired, be further purifiedby such conventional techniques as distillation, recrystallization orthe various chromatography techniques, notably column chromatography.

The starting materials employed in the above Methods may be prepared bya variety of methods well known for product compounds of this type. Byway of example, the following Methods G--P may be used.

Method G

In this method, the starting materials of formulae (III), (V) and (VII)in which Z represents an optionally substituted methylene group, Wrepresents a direct bond and the group --W--COOR³ is at the 5- or 6-position, that is to say compounds of formulae (IIIa), (Va) and (VIIa),may be prepared as illustrated by the following reaction scheme:##STR26##

In the above formulae, R⁴ is as defined above; R⁷ represents acarboxy-protecting group (e.g. as illustrated in relation to the groupR³ defined above); and R⁸ represents an alkyl, cycloalkyl or substitutedor unsubstituted aryl group as defined in relation to the correspondinggroups represented by substituents (b).

The corresponding compounds of formulae (VIIb), (Vb) and (IIIb);##STR27## (in which R⁴, R⁷ and X are as defined above), i.e. with thegroup --COOR⁷ at the 5- position, may be prepared by precisely the samereaction sequence as illustrated above but starting with a compound offormula (XIVa): ##STR28## in place of the compound of formula (XIV).

In the first step of this reaction, the starting material of formula(XIV) [or (XIVa)] is reacted with a dialkyl carbonate of formulaCO(OR²)₂ in the presence of a metal hydride, e.g. sodium hydride, toprepare the compound of formula (XV). This is then reacted with areducing agent, for example sodium borohydride, to reduce the ketonicoxygen to a hydroxy group in the compound of formula (XVI). This is thenreacted with a dehydrating agent, for example p-toluenesulfonic acid(p-TsOH), preferably under reflux and preferably in solution in, forexample, benzene, to give the compound of formula (XVIII). This is thensubjected to a Friedel-Crafts reaction with a compound of formula Cl₂CHOCH₃ or R⁸ COCl in the presence of aluminum chloride to give the acylcompound (VIIa) [or (VIIb)]. If desired, this may be reduced, forexample with sodium borohydride, to give the corresponding alcohol (Va)[or (Vb)] and, again if desired, this may be halogenated or sulfonylatedby conventional means to give the halogen or sulfonyl derivative offormula (IIIa) [or (IIIb)].

Method H

Starting materials of formula (III) and (V) in which Z¹ represents anoptionally substituted ethylene group and the group --COOR⁷ is at the 5-or 6- position, that is to say compounds of formulae (IIIc) and (Vc),and compounds of formula (VII) in which m is 1, R⁴ is a hydrogen atom, Wrepresents a direct bond and the group COOR³ is at the 5- or 6-position, that is to say compounds of formula (VIId), may be prepared asillustrated by the following reaction scheme: ##STR29##

In the above formulae, R⁴, R⁷ and X are as defined above; the group--COOR⁷ is at the 5- or 6- position; and the dotted lines mean that,where --COOR⁷ is at the 5- position, there is a double bond between the4- and 5- positions and a single bond between the 6- and 7- positions,and, where --COOR⁷ is at the 6- position, there is a double bond betweenthe 6- and 7- positions and a single bond between the 4- and 5-positions.

In the first step of this reaction, the compound of formula (VIIIc)[i.e. a compound of formula (VIIIa) or (VIIb) prepared as described inMethod G] is subjected to a Wittig reaction with a compound of formulaCH₃ OCH₂ P⁺ Ph₃ Cl⁻ (Ph is phenyl) in the presence of, for example,butyllithium (n-BuLi) to give the compound of formula (XVIII). This isthen hydrolized to give the aldehyde of formula (VIId), e.g. by means ofaqueous hydrochloric acid. If desired, this aldehyde may be reduced, forexample with sodium borohydride, to give the alcohol (Vc) and this maybe halogenated or sulfonylated to give the compound of formula (IIIc).

Method I

In this method, a compound of formula (IX) in which W represents adirect bond and the group --COOR³ is at the 5- or 6- position, i.e. acompound of formula (IXa), may be prepared as illustrated in thefollowing reaction scheme: ##STR30##

In the above formulae, R⁷, X, Y¹ and p are as defined above. The dottedline means a single or double bond between the 6- and 7- positions.

The starting material is ether a compound of formula (XV) or a compoundof formula (XVIII)--see Method G.

Where the starting material is a compound of formula (XV), this issubjected to a Celmmensen reduction using a metal, such as zinc ormercury, and an acid, such as hydrochloric acid or acetic acid, to givea compound of formula (XIX). Alternatively, the compound of formula(XIX) m ay be prepared from the compound of formula (XVII) by catalytichydrogenation, using, for example, palladium-on-carbon or platinum oxideas the catalyst.

The compound of formula (XVII) or (XIX) (which differ only in thepresence or absence of a double bond between the 6- and 7- positions) isthen subjected to a Friedel-Crafts reaction with a compound of formulaX--C(H₂)_(p) C(═O)--Cl to give the acyl compound of formula (XX). Thisis then reacted with imidazole (Y¹ H) to give the desired startingmaterial of formula (IXa).

Compounds of formula (IXB).: ##STR31## (in which R⁷, Y¹, p and thedotted line are as defined above) may be prepared by the same sequenceof reactions as illustrated above, but starting with the correspondingcompound of formula (XVa) or (XVIIa): ##STR32## (in which R⁷ is asdefined above).

Method J

Starting materials of formulae (VIIe), (Vd) and (IIID), that is to saycompounds of formula (VII), (V) and (III) in which W represents amethine group at the 6-position (and hence the broken lines bothrepresent single bonds), m is O and Z¹ represents a methylene groupwhich is unsubstituted or has at least one of substituents (b), may beprepared as illustrated by the following reaction scheme: ##STR33##

In the above formulae, R⁴, R⁵, R⁷ and X are as defined above. In thecompound of formula (XXI), the two groups represented by R⁷ may be thesame or different. Ac represents the acetyl group.

In the first step of this process, the compound of formula (XV) isreacted with a haloacetic, preferably bromoacetic, acid ester Br--CH₂COOR⁷, to prepare the compound of formula (XXI). This is then subjectedto hydrolysis, decarboxylation and then esterification to give thecompound of formula (XXII). Reduction of this compound of formula (XXII)by conventional means, e.g. with sodium borohydride, yields the hydroxycompounds of formula (XXIII), which is then acelytated, e.g. with aceticanhydride, preferably in the presence of a base (such as pyridine), togive the acetoxy compound of formula (XXIV). Reaction of this compoundwith a strong acid, such as p-toluenesulfonic acid, eliminates aceticacid and yields the methine compound of formula (XXV). This is thensubjected to a Friedel-Crafts reaction to introduce the group R⁴--C(═O)-- and give the compound of formula (VIIe). If desired, this maybe reduced, e.g. with sodium borohydride, to give the alcohol of formula(Vd), which may then, if desired, be halogenated or sulfonylated to givethe compound of formula (IIId).

Compounds corresponding to those of formulae (VIIe), (Vd) and (IIId) butin which the methine group represented by W is replaced by a methylenegroup can be prepared by subjecting the compound of formula (XXV) tocatalytic hydrogenation, e.g. in the presence of a catalyst such aspalladium-on-carbon or platinum oxide, and then subjecting the resultingcompound to the subsequent reactions in place of the compound of formula(XXV).

Additionally, corresponding compounds having the group --W--COOR⁷ (inwhich W represents a methine group or a methylene group) at the5-position may be prepared by carrying out the same series of reactions,but commencing with a compound of formula (XVa): ##STR34## (in which R⁷is as defined above) in place of the compound of formula (XV).

Method K

Starting materials of formula (III) where W is a direct bond, there is adouble bond between the 4- and 5- positions and Z¹ represents amethylene group, that is to say compounds of formula (IIIe), may beprepared as illustrated in the following reaction scheme: ##STR35##

In the above formulae, R³, R⁷ and X are as defined above.

In the first step of this scheme, the compound of formula (XXVI) isreduced with a suitable reducing agent, such as lithium aluminumhydride, to give the compound of formula (XXVII). This is thenhalogenated or sulfonylated by conventional means to give the compoundof formula (XXVIII). The compound of formula (XXVIII) is then subjectedto a Friedel-Crafts reaction to introduce a formyl group at the2-position and given the compound of formula (XXIX), which is thenoxidized (e.g. with sodium chlorite) and esterified to give the compoundof formula (IIIe).

Compounds corresponding to those of formula (IIIe) but in which thedouble bond is between the 6- and 7- positions and the group --CH₂ X isat the 6- position may be prepared by following the same sequence ofreactions as described above but starting with a compound correspondingto that of formula (XXVI) but in which the double bond is between the 6-and 7- positions and the group of formula --COOR³ is at the 6- position.

Also, tetrahydrothianaphthene derivatives (i.e. having single bonds bothbetween the 4- and 5- positions and between the 6- and 7- positions) andin which the group --CH₂ X is at either the 5- or the 6- position may beprepared by hydrogenating the compound of formula (XXVI) or its analoghaving the double bond between the 6- and 7- positions and the group--COOR³ at the 6- position, preferably employing palladium-on-carbon orplatinum oxide as the catalyst.

Method L

Compounds of formula (II) in which W represents a direct bond, Z¹represents an optionally substituted ethylene group, there is a doublebond between the 4- and 5- positions and the group --W--COOR³ is at the5-position, that is to say compounds of formula (IIIf), may be preparedas illustrated by the following reaction scheme: ##STR36##

In the above formulae, R³, R⁴, R⁷ and X are as defined above. In thecompound of formula (XXXI), the two groups represented by R³ may be thesame or different.

In the first step of this reaction, an elongated side chain isintroduced into the compound of formula (XXX) by reacting it with anoptionally substituted haloacetic (preferably chloroacetic) acid orester thereof, R⁴ CH(Cl)--COOR³, to give the compound of formula (XXXI).This is then hydrolized and decarboxylated to give the compound offormula (XXXII), which is reduced, preferably with sodium borohydride,and dehydrated with a strong acid (e.g. p-toluenesulfonic acid) to givethe compound of formula (XXXIII). This is then again reduced, this timepreferably with lithium aluminum hydride, to give the compound offormula (XXXIV), which is then halogenated or sulfonylated to give thecompound of formula (XXXV). This is subjected to a Friedel-Craftsreaction to give the compound o formula (XXXVI), which is then oxidized,preferably with sodium chlorite, and esterified, to give the desiredcompound of formula (IIIF).

If desired, a compound corresponding to the compound of formula (IIIf)but in which the double bond is between the 6- and 7- positions and thegroup of formula --CH(R⁴)--CH₂ X is at the 6- positions may be preparedby the same sequence of reactions but starting with a compoundcorresponding to the compound of formula (XXX) in which the ketonicoxygen is at the 7-position (instead of the 4- position) and the group--COOR³ is at the 6- position (instead of the 5-position).

If desired, the corresponding tetrahydrothianaphthene derivatives havingsingle bonds both between the 4- and 5-positions and between the 6- and7- positions and having the group --CH(R⁴)--CH₂ X at the 5- or the 6-position may be prepared by subjecting the compound of formula (XXXIII)or its analog having the double bond between the 6- and 7- positions andthe group --CH(R⁴)--COOR³ at the 6- position to catalytic hydrogenation,preferably employing palladium-on-carbon or platinum oxide as thecatalyst, to reduce the 4,5 or 6,7 double bond and then subjecting theresulting compound to the same sequence of reactions as the compound offormula (XXXIII).

Method M

Compounds of the formula (VII) in which W represents a direct bond, thegroup --W--COOR⁷ is at the 2- position, m is O, the --CH₂ -- group isoptionally substituted, the resulting group --CH(R⁴)--COR⁵ is at the 5-position and there is a double bond between the 4- and the 5- positions,that is to say compounds of formula (VIIf), may be prepared asillustrated in the following reaction scheme: ##STR37##

In the above formulae, R³, R⁴, R⁵, R⁷ and X' are as defined above.

In the first stage of this process, the compound formula (XXXIII) (whichmay have been prepared as described above in relation to Method L) isconverted into its corresponding acid halide, preferably the acidchloride, the compound of formula (XXXVII), by reaction with ahalogenating agent, e.g. thionyl chloride or phosphorus pentachloride.This is then reacted with a Grignard reagent, R⁵ MgX', to give theketonic compound (XXXXVIII), which is then subjected to a Friedel-Craftsreaction, to give the compound of formula (XXXIX). The resultingcompound is then first oxidized, e.g. with sodium chlorite, and thenesterified, to give the desired compound of formula (VIIf).

A compound corresponding to the compound of formula (VIIf), but in whichthe double bond is between the 6- and 7- positions and the group offormula --CH(R⁴)--COR⁵ is at the 6- position, may be prepared bycarrying out the same sequence of reactions as described above butstarting with a compound corresponding to the compound of formula(XXXIII) but with the double bond between the 6- and 7- positions andthe group of formula --CH(R⁴)--COOR³ at the 6- position (this itself maybe prepared as described in relation to the corresponding compound inMethod L).

The corresponding tetrahydrothianaphthene compounds having double bondsboth between the 4- and 5- positions and between the 6- and 7- positionsand having the group of formula --CH(R⁴)COR⁵ at either the 5- or the 6-position may be prepared by the same reactions as described above,except that the starting material of formula (XXXIII) or its analoghaving the double bond between the 6- and 7- positions and the group offormula --CH(R⁴)--COOR³ at the 6- position is hydrogenated (preferablyin the presence of palladium-on-carbon or platinum oxide as catalyst)and the resulting hydrogenated compound is then subjected to the abovereaction sequence.

Method N

Compounds of formula (IX) in which W represents a direct bond, p is O,the double bond is between the 4- and 5- positions and the group --COOR³is at the 2- position, that is to say compounds of formula (IXb), may beprepared as illustrated by the following reaction scheme: ##STR38##

In the above formulae, R⁷ and Y¹ are as defined above.

In the first step of this reaction, the compound of formula (XXVIa) isconverted to its acid halide, e.g. the acid chloride (XL), by reactionwith a halogenating agent, for example thionyl chloride, phosphoruspentachloride or phosphorus oxychloride. The resulting acid halide (XL)is then subjected, in turn, to the following reactions: reaction with aGrignard reagent of formula CH₃ MgBr to give the ketonic compound (XLI);a Friedel-Crafts reaction to give the aldehyde (XLII); oxidation,preferably with sodium chlorite, and then esterification to give theester (XLIII); bromination to give the bromide (XLIV); and finallyreaction with imidazole (Y¹ H) to give the compound of formula (IXb).

The corresponding compound in which the double bond is between the 6-and 7- positions and the group --C(═O)--CH₂ Y¹ is at the 6- position maybe prepared by the same sequence of reactions, but starting with acompound corresponding to the compound of formula (XXVIa) but in whichthe double bond is between the 6- and 7- positions and the group --COOHis at the 6- position.

The corresponding tetrahydrothianaphthene compounds having single bondsboth between the 4- and 5- positions and between the 6- and 7- positionsand having the group --C(═O)--CH₂ Y¹ at either the 5- position or the 6-position may be prepared by hydrogenating the compound of formula(XXVIa) or its analog having the double bond between the 6- and 7-positions and the carboxyl group at the 6- position, preferably usingpalladium-on-carbon or platinum oxide as the catalyst.

Method O

Compounds of formula (III) in which W represents a vinylene group, thegroup --W--COOR³ is at the 2- position, there is a double bond betweenthe 4- and 5- positions, Z¹ represents a methylene group and the group--CH₂ X (i.e. --Z¹ --X) is at the 5- position, that is to say compoundsof formula (IIIg), may be prepared by a Wittig reaction from thecompound o formula (XXIX) (see Method K), as shown in the followingreaction: ##STR39##

The corresponding compound having a double bond between the 6- and 7-positions and having the group --CH₂ X at the 6- position may beprepared by the same reaction but starting with an analog of thecompound of formula (XXIX) in which the double bond and the group --CH₂X are at those positions.

Similarly, tetrahydrothianaphthene derivatives having double bonds bothbetween the 4- and 5- positions and between the 6- and 7- positions andhaving the group --CH₂ X at either the 5- position or the 6- positionmay be prepared by first hydrogenating the compound of formula (XXIX) orits aforementioned analog before carrying out the Wittig reaction.

Method P

Compounds of formula (III) in which W represents a methylene group, thegroup --W--COOR³ is at the 2- position, a double bond is present betweenthe 4- and 5- positions, Z¹ represents a methylene group and the group--CH₂ X (i.e. --Z¹ --X) is at the 5- position, that is to say compoundsof formula (IIIh), may be prepared as illustrated by the followingreaction scheme: ##STR40##

In the above formulae, X and pH are as defined above.

In the first step of this reaction, the compound of formula (XXIX) issubjected to the Wittig reaction to form a double bond in the side chainof the 2- position and give the compound of formula (XXLV). This is thenoxidized, suitably with pyridinium chlorochromate, to give the desiredcompound of formula (IIIh).

Compounds corresponding to the compounds of formula (IIIh) but in whichthere is a double bond between the 6- and 7- positions and in which thegroup --CH₂ X is at the 6- position may be prepared by the same sequenceof reactions, but starting with an analog of the compound of formula(XXIX) in which the double bond is present between the 6- and 7-positions and the group --CH₂ X is present at the 6- position.

Corresponding tetrahydrothianaphthene derivatives having single bondsboth between the 4- and 5- positions and between the 6- and 7- positionsand having the group --CH₂ X at either the 5- position or the 6-position may be prepared by first halogenating the compound of formula(XXIX) or its aforementioned analog prior to carrying out the Wittigreaction and then the oxidation

In all of the foregoing Methods G-P, starting materials in which R¹and/or R² represents an alkyl group may be prepared by exactly the samemethods but employing corresponding starting materials having one ormore alkyl substituents at the appropriate position.

Where starting materials are prepared as esters, these can, if desired,be converted before use by conventional hydrolysis reactions to the freeacid.

The compounds of the present invention may contain one or moreasymmetric carbon atoms and thus can exist in the form of variousoptical isomers. If required, individual optical isomers may be preparedby employing specific isomers of the starting materials and/or bystereospecific synthesis techniques. Alternatively, if a mixture ofisomers is prepared by any of the above reactions, the individualisomers can be obtained by conventional optical resolution techniques.Alternatively, a mixture of the isomers may be employed. Although all ofthe isomers are represented above by a single structural formula, thepresent invention envisages both the individual isolated isomers as wellas mixtures thereof.

The compounds of the present invention have been found to have excellentability to inhibit blood platelet aggregation and to inhibit theactivity of TXA₂ synthetase, as a result of which they have excellentanti-thrombotic activity, as demonstrated by pharmacological tests,including those reported hereafter.

Thus, the compounds of the invention have shown 100% inhibition ofcollagen-induced platelet aggregation in rabbit platelet-rich plasma atconcentrations of the order of 10⁻⁵ g/ml and 50% inhibition of thebiosynthesis of TXA₂ at molar concentrations of the order of 10⁻⁸. Onthe other hand, the inhibitory activities against cyclooxygenase andprostacyclin synthetase are very weak, thus indicating that thecompounds of the present invention are relatively inactive against otherenzymes of metabolic importance, which is an advantage. In in vivoexperimental systems, the compounds of the present invention havedemonstrated, on oral administration, considerable preventive effectagainst mortality from thrombotic disorders in mice and rabbits inducedby intravenous injection of arachidonic acid. These tests are all wellrecognized as providing good experimental models to demonstrateanticipated activity in human beings.

In particular, the lack of activity against cyclooxygenase andprotacyclin synthetase demonstrate that the compounds of the inventiondo not inhibit the synthesis of other prostaglandin derivatives.

Accordingly, the compounds of the present invention are expected to b evaluable for the therapy and prophylaxis of diseases and disorderscaused by an imbalance in the blood level of TXA₂, for exampleinflammation, hypertension, thrombosis, cerebral haemorrhages andasthma, and are expected to be especially useful in the treatment orprophylaxis of thromboembolisms in mammals, including humans. Forexample, they are expected to be useful in the treatment and prophylaxisof myocardial infarction, cerebral vascular thrombosis and ischemicperipheral blood vessel diseases, as well as in the treatment andprophylaxis of postoperative thrombosis and to accelerate the dilationof transplanted blood vessels after an operation.

The compounds of the invention maybe administered by any suitable route,oral or parenteral, and may be formulated accordingly, for example: fororal administration as tablets, capsules, powders, granulessuppositories or as injectible solutions or suspensions for subcutaneousof intravenous injection.

The compounds of the invention may be formulated with conventionalpharmaceutical carriers or diluents or may be administered as such.

The amount of the compound of the invention to be administered willvary, depending upon the nature and severity of the disease or disorderto be treated, the age, body weight, symptoms and condition of thepatient and the mode of administration. However, by way of guidance, thedose for an adult human being would be expected to be from 50 to 1800 mgper day, which is preferably administered in divided doses, e.g. about 2or 3 times per day.

The preparation of certain compounds of the invention is furtherillustrated by the following Examples 1-45, whilst the preparation ofcertain of the starting materials used in these Examples is illustratedin the subsequent Preparations. The biological activity of the compoundsof the invention is illustrated in Experiments 1 and 2. In the nuclearmagnetic resonance spectra, tetramethylsilane was used as the internalstandard in all Examples.

EXAMPLE 1 Methyl4,5-dihydro-2-(1-imidazolyl)methylthianaphthene-6-carboxylate

1(a) 0.14 g of sodium borohydride was added to a solution of 0.75 g ofmethyl 2-formyl-4,5-dihydrothianaphthene-6-carboxylate in a mixture of 4ml each of methanol and tetrahydrofuran at 3° C., and the mixture wasstirred for 30 minutes. At the end of this time, the reaction mixturewas concentrated by evaporation under reduced pressure. The residue wasextracted with aqueous ethyl acetate, and the extract was washed with anaqueous solution of sodium chloride, dried over anhydrous sodiumsulfate, filtered and evaporated to dryness under reduced pressure, togive 0.75 g of methyl4,5-dihydro-2-hydroxymethylthianaphthene-6-carboxylate.

1(b) 0.73 ml of a solution of thionyl chloride in 10 ml of methylenechloride was added dropwise to a solution of 2.98 g of imidazole and 20mg of 4-dimethylaminopyridine in 60 ml of methylene chloride, and themixture was stirred for 30 minutes. A solution of 0.75 g of methyl4,5-dihydro-2-hydroxymethylthianaphthene-6-carboxylate [prepared asdescribed in step (a) above] in 10 ml of methylene chloride was addeddropwise to the solution, and the reaction mixture was stirred overnightat room temperature. The reaction mixture was then concentrated byevaporation under reduced pressure. The residue was extracted with amixture of a saturated aqueous solution of sodium bicarbonate and ethylacetate. The extract was washed 5-6 times with water, dried overanhydrous sodium sulfate, filtered and concentrated by evaporation underreduced pressure. The resulting syrupy substance was purified by columnchromatography through silica gel, eluted with a 50:1:1 by volumemixture of ethyl acetate, ethanol and triethylamine, to give 0.21 g ofthe title compound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.80 (3H, singlet);5.22 (2H, singlet).

EXAMPLE 2 Sodium4,5-dihydro-2-(1-imidazolyl)methylthianaphthene-6-carboxylate and itshydrate

0.21 g of methyl4,5-dihydro-2-(1-imidazolyl)methylthianaphthene-6-carboxylate (preparedas described in Example 1) was hydrolyzed in a solution of sodiumhydroxide in aqueous ethanol. The ethanol was distilled off underreduced pressure. The resulting aqueous solution was washed with diethylether and then evaporated to dryness. The resulting solid residue wasreprecipitated from methanol-diethyl ether, to afford 0.12 g of thetitle compound as a pale yellow amorphous powder.

Infrared Absorption Spectrum (Nujol-trade mark-mull) ν_(max) cm ⁻¹ :1650, 1550.

Elemental analysis: Calculated for C₁₃ H₁₁ N₂ O₂ SNa.H₂ O: C, 51.99%; H,3.79%; N, 9.33%; S, 10.68%. Found: C, 52.11%; H, 3.78%; N, 9.43%; S,10.25%.

The amorphous solid obtained as described above was recrystallized from80% v/v aqueous methanol-acetone to give the corresponding anhydride aspale yellow needles (m.p. >300° C.).

Elemental Analysis: Calculated for C₁₃ H₁₁ N₂ O₂ SNa: C, 55.315; H,3.93%; N, 9.92% S, 11.36%. Found: C, 55.53%; H, 3.96%; N, 10.08%; S,11.24%.

EXAMPLE 3 Methyl4,5-dihydro-2-[α-(1-imidazolyl)benzyl]thianaphthene-6-carboxylate

0.40 g of methyl 2-benzoyl-4,5-dihydrothianaphthene-6-carboxylate wasreduced with sodium borohydride in the same manner as described inExample 1(a), and then an imidazolyl group was introduced by the methoddescribed in Example 1(b). The reaction mixture was then concentrated byevaporation under reduced pressure. The residue was extracted with amixture of a saturated aqueous solution of sodium bicarbonate and ethylacetate. The extract was washed 5-6 times with water, dried overanhydrous sodium sulfate, filtered and concentrated by evaporation underreduced pressure. The resulting crude oily substance thus obtained wassubjected to column chromatography through silica gel, using ethylacetate as the eluent, to afford 0.21 g of the title compound.

Nuclear magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.79 (3H, singlet);6.65 (2H, singlet).

EXAMPLE 4 Sodium4,5-dihydro-2-[α-(1-imidazolyl)benzyl]thianaphthene-6-carboxylatetrihydrate

0.21 g of methyl4,5-dihydro-2-[α-(1-imidazolyl)benzyl]thanaphthene-6-carboxylate(prepared as described in Example 3) was hydrolyzed in a solution ofsodium hydroxide in aqueous ethanol. The ethanol was then distilled offunder reduced pressure. The resulting aqueous solution was washed withdiethyl ether and then evaporated to dryness. The resulting powder wasreprecipitated from ethanol-diethyl ether to afford 70 mg of the titlecompound as a colorless, amorphous powder.

Infrared Absorption Spectrum (Nujol mull) ν_(max) cm⁻¹ : 1690, 1460.

Elemental analysis: Calculated for C₁₉ H₁₅ N₂ O₂ SNa.3H₂ O: C, 55.33%;H, 5.13%; N, 6.79%; S, 7.77%. Found: C, 55.23%; H, 4.85%; N, 7.05%; S,7.79%.

EXAMPLE 5 Methyl2-[2-(1-imidazolyl)ethyl]-4,5-dihydrothianaphthene-6-carboxylate 5(a)Methyl2-[2-(1-imidazolyl)-1-oxoethyl]-4,5-dihydrothianaphthene-6-carboxylate

A Friedel-Crafts reaction was carried out using 15.0 g of methyl4,5-dihydrothianaphthene-6-carboxylate, 20.6 g of aluminum chloride and8.3 ml of bromoacetyl chloride. The reaction mixture was then pouredinto ice-water and stirred for 1hour. The mixture was then extractedwith methylene chloride. The extract was washed with aqueous sodiumchloride, dried over anhydrous sodium sulfate, filtered and thenevaporated to dryness under reduced pressure, to obtain a crudecrystalline substance containing methyl2-(2-bromo-1-oxoethyl)-4,5-dihydrothianaphthene-6-carboxylate. The crudecrystalline substance thus obtained was dissolved in a mixture of 300 mlof methanol and 150 ml of tetrahydrofuran. 18.4 g of imidazole wereadded to the resulting solution, and the mixture was heated under refluxfor 2 hours. At the end of this time, the reaction mixture wasconcentrated by evaporation under reduced pressure. The residue wasdissolved in ethyl acetate, and the resulting solution was washed inturn with a saturated aqueous solution of sodium bicarbonate and with anaqueous solution of sodium chloride. The solution was then filtered andconcentrated by evaporation under reduced pressure. The resultingresidue was subjected to silica gel column chromatography, using a40:1:1 by volume mixture of ethyl acetate, ethanol and triethylamine asthe eluent, to afford 20.16 g of the title compound as an oilysubstance.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.85 (3H, singlet);5.20 (2H, singlet).

5(b) Methyl2-[2-(1-imidazolyl)-1-methylthio-(thiocarbonyl)oxyethyl]-4,5-dihydrothianaphthene-6-carboxylate

2.01 g of methyl 2-[2-(1-imidazolyl)-1-oxoethyl]-4,5-dihydrothianaphthene-6-carboxylate [prepared as described in step(a) above] were reduced with sodium borohydride in the same manner asdescribed in Example 1(a), to obtain 1.72 g of an alcohol. This wasdissolved in tetrahydrofuran, 0.30 g of sodium hydride was added at 3°C. to the resulting solution, and the mixture was stirred at 50° C. for1 hour. The mixture was then cooled by allowing it to stand at roomtemperature. 1.7 ml of carbon disulfide and 1.76 ml of methyl iodidewere added in that order, and the mixture was stirred at roomtemperature for 20 minutes. At the end of this time, the reactionmixture was poured into a mixture of ice-water and 0.39 ml of glacialacetic acid and extracted with ethyl acetate. The extract was washed inturn with a saturated aqueous solution of sodium bicarbonate and with anaqueous solution of sodium chloride. The solution was then dried overanhydrous sodium sulfate and concentrated by evaporation under reducedpressure. The resulting residue was subjected to silica gel columnchromatography, using an 8:1;1 by volume mixture of ethyl acetate,ethanol and triethylamine as eluent, to afford 1.03 g of the titlecompound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 2.40 (3H, singlet);3.79 (3H, singlet).

5(c) Methyl2-[2-(1-imidazolyl)ethyl]-4,5-dihydrothianaphthene-6-carboxylate

1.00 g of methyl2-[2-(1-imidazolyl)-1-methylthio(thiocarbonyl)oxyethyl]-4,5-dihydrothianaphthene[prepared as described in step (b) above] was dissolved in a mixture of15 ml of tetrahydrofuran and 10 ml of toluene. 1.0 ml of tributyltinhydride was added to the solution in the presence of a catalytic amountof azobisisobutyronitrile, and the mixture was heated under reflux for 1day under an atmosphere of nitrogen. At the end of this time, thereaction mixture was condensed by distilling off the solvent underreduced pressure, and a solution of the residue in acetonitrile waswashed with hexane. The acetonitrile was then removed by distillationunder reduced pressure, and the residue was subjected to silica gelcolumn chromatography using a 30:1:1 by volume mixture of ethyl acetate,ethanol and triethylamine as the eluent, to afford 0.51 g of the titlecompound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.16 (2H, triplet);3.80 (2H, singlet); 4.19 (2H, triplet); 7.42 (1H, singlet).

EXAMPLE 6 Sodium2-[2-(1-imidazolyl)ethyl]-4,5-dihydrothianaphthene-6-carboxylate

0.45 g of methyl2-[2-(1-imidazolyl)ethyl]-4,5-dihydrothianaphthene-6-carboxylate(prepared as described in Example 5) was hydrolyzed with sodiumhydroxide in the same manner as described in Example 2, to obtain asolid, which was reprecipitated from methanol and diethyl ether, toafford 0.37 g of the title compound as a colorless, amorphous powder.

Infrared Absorption Spectrum (Nujol mull) ν_(max) cm⁻¹ : 1630, 1560.

Elemental analysis: Calculated for C₁₄ H₁₃ N₂ O₂ SNa: C, 56.75%; H,4.42%,; N, 9.45%; S, 10.82%. Found: C, 56.58%; H, 4.70%; N, 9.44%; S,10.59%.

EXAMPLE 7 Methyl4,5,6,7-tetrahydro-2-(1-imidazolyl)methylthianaphthene-6-carboxylate

Using the same procedure as described in Example 1, 0.20 g of the titlecompound was obtained as an oily substance from 0.34 g of2-formyl-4,5,6,7-tetrahydrothianaphthene-6-carboxylate.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.77 (3H, singlet);5.20 (2H, singlet).

EXAMPLE 8 Sodium4,5,6,7-tetrahydro-2-(1-imidazolyl)methylthianaphthene-6-carboxylate

0.30 g of methyl4,5,6,7-tetrahydro-2-(1-imidazolyl)methylthianaphthene-6-carboxylate(prepared as described in Example 7) was hydrolyzed with sodiumhydroxide in the same manner as described in Example 2, to obtain asolid, which was reprecipitated from ethanol-diethyl ether, to afford0.19 g of the title compound as a colorless, amorphous powder.

Infrared Absorption Spectrum (Nujol mull) ν_(max) cm⁻¹ : 1560.

Elemental analysis:

Calculated for C₁₃ H₁₃ N₂ O₂ SNa: C, 54.92%; H, 46.09%; N, 9.85%; S,11.28%. Found: C, 54.68%; H, 45.87%; N, 9.91%; S, 11.45%.

EXAMPLE 9 Methyl2-[2-(1-imidazolyl)ethyl]-4,5,6,7-tetrahydrothianaphthene-6-carboxylate9(a) Methyl2-[2-(1-imidazolyl)-1-oxoethyl]-4,5,6,7-tetrahydrothianaphthene-6-carboxylate

Using the same procedure as described in Example 5(a), 0.54 g of thetitle compound was obtained as an oily substance from 0.80 g of methyl4,5,6,7-tetrahydrothianaphthene-6-carboxylate.

Nuclear magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.74 (3H, singlet);5.22 (2H, singlet).

9(b) Methyl2-[2-(1-imidazolyl)-1-methylthio(thiocarbonyl)oxyethyl]-4,5,6,7-tetrahydrothianaphthene6-carboxylate

Using the same procedure as described in Example 5(b), 0.42 g of thetitle compound was obtained as an oily substance from 0.54 g of theketone prepared as described in step (a) above.

Nuclear magnetic Resonance Spectrum (CDCl₃) δppm: 2.38 (3H, singlet);3.77 (3H, singlet).

2(c) Methyl2-[2-(1-imidazolyl)ethyl]-4,5,6,7-tetrahydrothianaphthene-6-carboxylate

0.41 g of the xanthate ester [prepared as described in step (b) above]was subjected to a free radical reduction with tributyltin hydride inthe same manner as described in Example 5(c), to obtain 0.28 g of thetitle compound.

Nuclear magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.18 (2H, triplet);3.79 (3H, singlet); 4.20 (2H, triplet).

EXAMPLE 102-(2-(1-Imidazolyl)ethyl]-4,5,6,7-tetrahydrothianaphthene-6-carboxylicacid hydrochloride

A solution of 0.25 g of methyl2-[2-(1-imidazolyl)ethyl]-4,5,6,7-tetrahydrothianaphthene-6-carboxylate(prepared as described in Example 9) in a mixture of 5 ml ofconcentrated hydrochloric acid and 5 ml of glacial acetic acid washeated under reflux for 4 hours. At the end of this time, the reactionmixture was evaporated to dryness by distilling off the solvent underreduced pressure, and the resulting solid residue was recrystallizedfrom a mixture of ethanol and diethyl ether, to afford 0.19 g of thetitle compound as a colorless, amorphous powder.

Infrared Absorption Spectrum (Nujol mull) ν_(max) cm⁻¹ : 1720.

Elemental analysis: Calculated for C₁₄ H₁₆ N₂ O₂ S.HCl: C, 53.76%; H,5.48%, N, 8.96%; S, 10.25%; Cl, 11.33%. Found: C, 53.72%; H, 5.73%; N,9.01%; S, 9.95%; Cl, 11.30%.

EXAMPLE 114,5,6,7-Tetrahydro-2-(1-imidazolyl)methyl-6-methoxycarbonylmethylidenethianaphthene

Using the same procedure as described in Example 1, 0.39 g of the titlecompound was obtained as an oily substance from 1.50 g of2-formyl-4,5,6,7-tetrahydro-6-methoxycarbonylmethylidenethianaphthene.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.68 (3H, singlet);5.20 (2H, singlet); 6.25 (1H, singlet); 6.73 (1H, singlet).

EXAMPLE 12 Sodium salt of4,5,6,7-tetrahydro-2-(1-imidazolyl)methyl-6-carboxymethylidenethianaphthen

0.29 g of4,5,6,7-tetrahydro-2-(1-imidazolyl)methyl-6-methoxycarbonylmethylidenethianaphthene(prepared as described in Example 11) was hydrolyzed with sodiumhydroxide in the same manner as described in Example 2 to obtain asolid, which was reprecipitated from ethanol-diethyl ether, to afford0.20 g of the title compound as a pale yellow, amorphous powder.

Infrared Absorption Spectrum (Nujol mull) ν_(max) cm⁻¹ : 1580.

Elemental analysis: Calculated for C₁₄ H₁₃ N₂ O₂ SNa: C, 56.75%; H,4.42%; N, 9.45% S, 10.82%. Found: C, 57.03%; H, 4.18%; N, 9.40%; S,11.08%.

EXAMPLE 13 Methyl4,5,6,7-tetrahydro-2-[(3-pyridyl)methyl]thianaphthene-6-carboxylate13(a) Methyl4,5-dihydro-2-[(hydroxy)(3-pyridyl)methyl]thanaphthene-6-carboxylate

12 ml of a 15% w/v solution of butyllithium in hexane were added to asolution of 2.17 ml of 3-bromopyridine in 40 ml of diethyl ether at -78°C. under an atmosphere of nitrogen, and the mixture was stirred for 30minutes. A solution of 2.5 g of methyl2-formyl-4,5-dihydrothianaphthene-6-carboxylate in a mixture of 20 mleach of diethyl ether and tetrahydrofuran was then added dropwisethereto. The mixture was then warmed up to room temperature over aperiod of about one hour and then poured into an aqueous solution ofammonium chloride. The mixture was extracted with ethyl acetate, and theextract was washed with an aqueous solution of sodium chloride, driedover anhydrous sodium sulfate and concentrated by evaporation underreduced pressure. The residue was subjected to silica gel columnchromatography, using ethyl acetate is the eluent, to afford 1.61 g ofthe title compound as an oily substance.

Nuclear magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.80 (3H, singlet);5.94 (1H, singlet); 6.65 (1H, singlet).

13(b) Methyl4,5,6,7-tetrahydro-2-[(3-pyridyl)methyl]thianaphthene-6-carboxylate

1.0 g of methyl4,5-dihydro-2[(hydroxy)(3-pyridyl)methyl]thianaphthene-6-carboxylate[prepared as described in step (a) above] in solution in ethanol wasreduced in the presence of 3.48 ml of a 1N aqueous solution ofhydrochloric acid over 2.0 g of a 10% w/w palladium-on-carbon catalystand in an atmosphere of hydrogen. When the reduction was complete, thereaction mixture was adjusted to a pH value of 8 by the addition of anaqueous solution of sodium bicarbonate. The mixture was then filtered,and the filtrate was concentrated by evaporation under reduced pressure.The resulting residue was dissolved in ethyl acetate, and the solutionwas washed with an aqueous solution sodium chloride. The solution wasthen dried over anhydrous sodium sulfate, filtered and concentrated byevaporation under reduced pressure. The resulting residue was purifiedby silica gel column chromatography, using a 1:2 by volume mixture ofhexane and ethyl acetate as the eluent, to afford 0.15 g of the titlecompound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.71 (3H, singlet);4.08 (2H, singlet); 6.44 (1H, singlet).

EXAMPLE 144,5,6,7-Tetrahydro-2-[(3-Pyridyl)methyl]thianaphthene-6-carboxylatehydrochloride

0.15 g of methyl4,5,6,7-tetrahydro-2-[(3-pyridyl)methyl]thianaphthene-6-carboxylate(prepared as described in Example 13) was dissolved in a mixture of 2 mleach of concentrated hydrochloric acid and glacial acetic acid, and themixture was heated under reflux for 9 hours. At the end of this time,the reaction mixture was evaporated to dryness under reduced pressure,and the resulting residue was recrystallized from ethanol-diethyl ether,to afford 0.12 g of the title compound as colorless needles, melting at205°-208° C.

Elemental analysis: Calculated for C₁₅ H₁₅ NO₂ S.HCl; C, 58.15%; H,5.21%, N, 4.52%; S, 10.35%; Cl, 11.48%. Found: C, 57.89%; H, 5.45%; N,4.50%; S, 10.41%; Cl, 11.55%.

EXAMPLE 15 Methyl2-[2-(1-imidazolyl)vinylene]-4,5-dihydrothianaphthene-6-carboxylate

1.02 g of methyl2-[2-(1-imidazolyl)-1-oxoethyl]-4,5-dihydrothianaphthene-6-carboxylate[prepared as described in Example 5(a)] was reduced with sodiumborohydride in the same manner as described in Example 1 to obtain 0.87g of the corresponding alcohol. A solution of this alcohol in 100 ml oftoluene was heated under reflux for 2 hours in the presence of 0.59 g ofp-toluenesulfonic acid monohydrate. At the end of this time, thereaction mixture was poured into a saturated aqueous solution of sodiumbicarbonate and extracted with ethyl acetate. The extract was washedwith an aqueous solution of sodium chloride, dried over anhydrous sodiumsulfate, filtered and concentrated by evaporation under reducedpressure. The resulting residue was subjected to silica gel columnchromatography, using a 40:1;1 by volume mixture of ethyl acetate,ethanol and triethylamine as the eluent, to afford 0.58 g of the titlecompound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3,79 (3H, singlet);65.-7.3 (6H, multiplet); 7.75 (1H, singlet).

EXAMPLE 16 Sodium2-[2-(1-imidazolyl)vinylene]-4,5-dihydrothianaphthene-6-carboxylate

0.38 g of methyl2-[2-(1-imidazolyl)vinylene]-4,5-dihydrothianaphthene-6-carboxylate(prepared as described in Example 15) was hydrolyzed with sodiumhydroxide in the same manner as described in Example 2, and a solidproduct was reprecipitated from a mixture of ethanol and diethyl ether,to afford 0.29 g of the title compound as a colorless, amorphous powder.

Infrared Absorption Spectrum (Nujol mull) ν_(max) cm⁻¹ ; 1635, 1560.

Elemental analysis: Calculated for C₁₄ H₁₁ N₂ O₂ SNa: C, 57.14%; H,3.77%; N, 9.52%; S, 10.89%. Found: C, 56.89%; H, 3.88%; N, 9.56%; S,11.21%.

EXAMPLE 176-[4,5,6,7-Tetrahydro-2-(1-imidazolyl)methylthianaphthene]carboxylicacid hydrochloride

A solution of 2.90 g of methyl4,5,6,7-tetrahydro-2-(1-imidazolyl)methylthianaphthene-6-carboxylate(prepared as described in Example 7) in 30 ml of concentratedhydrochloric acid and 30 ml of glacial acetic acid was heated underreflux for 3 hours. At the end of this time, the reaction mixture wasevaporated to dryness under reduced pressure, and the residue wastreated to give a crude crystalline substance, which was thenrecrystallized from 95% v/v aqueous ethanol-acetone to give 22.55 g ofthe title compound as colorless needles, melting at 197°-198° C.

Infrared Absorption Spectrum (KBr) ν_(max) cm⁻¹ ; 1720.

Elemental Analysis: Calculated for C₁₃ h₁₄ N₂ O₂ S.HCl; C, 52.26%; H,5.06%; N, 9.38%; S, 10.73%; Cl, 11.87%. Found: C, 52.15%; H, 5.09%; N,9.31%; S, 10.63%; Cl, 11.77%.

EXAMPLE 18 Methyl6,7-dihydro-2-[(1-imidazolyl)methyl]-thianaphthene-5-carboxylate

A solution of 0.78 ml of thionyl chloride in 4 ml of methylene chloridewas added to a solution of 2.91 g of imidazole in methylene chloride,and the mixture was stirred for 30 minutes. A solution of 0.96 g ofmethyl 6,7-dihydro-2-(hydroxymethyl)thianaphthene-5-carboxylate in 15 mlof methylene chloride was then added dropwise thereto. The reactionmixture was stirred for 15 hours at room temperature, after which timethe solvent was removed by distillation under reduced pressure. Theresidue obtained was dissolved in ethyl acetate, and the solution waswashed, in turn, with an aqueous solution of sodium bicarbonate and withan aqueous solution of sodium chloride. It was then dried over anhydroussodium sulfate. The solvent was then removed by evaporation underreduced pressure, and the residue was subjected to silica gel columnchromatography, using a 20:1:1 by volume mixture of ethyl acetate,ethanol and triethylamine as the eluent, to give 0.76 g of the titlecompound. This product was recrystallized from acetone-hexane to affordpale yellow needles, melting at 87.0-89.0° C.

EXAMPLE 19 Sodium5-{6,7-dihydro-2-[(1-imidazolyl)methyl]-thianaphthene}carboxylatehemihydrate 0.13 g of methyl6,7-dihydro-2-[(1-imidazolylmethyl)]thianaphthene-5-carboxylate(prepared as described in Example 18) was hydrolysed with sodiumhydroxide in ethanol by conventional means. The ethanol was distilledoff under reduced pressure, and the residual aqueous phase was washedwith diethyl ether and then evaporated to dryness under reducedpressure. The resulting product was recrystallized from methanol-acetoneto afford 0.10 g of the title compound as pale green needles, notmelting at 260° C.

Elemental analysis: Calculated for C₁₃ H₁₁ N₂ O₂ SNa.1/2 H₂ O: C,53.60%; H, 4.15%; N, 9.62%; S, 11.01%. Found: C, 53.77% H, 3.97%; N,9.19%; S, 11.10%.

EXAMPLE 20 Methyl4,5,6,7-tetrahydro-2-[(1-imidazolyl)methyl]thianaphthene-5-carboxylate

0.30 g of methyl6,7-dihydro-2-[(1-imidazolyl)methyl]thianaphthene-5-carboxylate(prepared as described in Example 18) was catalytically hydrogengated inthe presence of 1.0 g of 10% w/w palladium-on-carbon and 1.15 ml of 1Naqueous hydrochloric acid in a hydrogen atomsphere. At the end of thistime, the reaction mixture was adjusted to a pH value of 8 by theaddition of an aqueous solution of sodium bicarbonate; it was thenfiltered. The filtrate was concentrated by evaporation under reducedpressure, and the residue was dissolved in ethyl acetate. The resultingsolution was washed with an aqueous solution of sodium chloride anddried over anhydrous sodium sulfate. It was then filtered andconcentrated by evaporation under reduced pressure, to afford 0.12 g ofthe title compound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.70 (3H, singlet);5.14 (2H, singlet); 6.65 (1H, singlet).

EXAMPLE 215-}4,5,6,7-tetrahydro-2-[(1-imidazolyl)methyl]thianaphthene}carboxylicacid hydrochloride 1/4 hydrate

A solution of 0.12 g of methyl4,5,6,7-tetrahydro-2[(1-imidazolyl)methyl]thianaphthene-5-carboxylate(prepared as described in Example 20) in 3 ml of concentratedhydrochloric acid and 3 ml of glacial acetic acid was heated underreflux for 4 hours. At the end of this time, the reaction mixture wasevaporated to dryness by distillation of the solvent under reducedpressure. The residue was recrystallized from a mixture of ethanol anddiethyl ether, to afford 0.09 g of the title compound as colorlessscaley crystals, melting at 213.0°-215.0° C.

Elemental analysis: Calculated for C₁₃ H₁₄ N₂ O₂ S.HCl.1/4 H₂ O: C,51.48%; H, 5.15%; N, 9.23%; S, 10.57%; Cl, 11.69%. Found: C, 51.17%; H,5.16%; N, 9.09%; S, 10.40%; Cl, 11.82%.

EXAMPLE 22 Methyl6,7-dihydro-2-[α(1-imidazolyl)benzyl]-thianaphthene-5-carboxylate

A solution of 1.22 ml of thionyl chloride in 10 ml of methylene chloridewas added to a solution of 4.92 g of imidazole in 20 ml of methylenechloride and, after 30 minutes, a solution of 1.67 g of methyl2-[(hydroxy)-(phenyl)methyl]thanaphthene-5-carboxylate in 30 ml ofmethylene chloride was added dropwise thereto under a nitrogenatmosphere. After 10 minutes, the reaction mixture was concentrated andtreated in the same manner as described in Example 18. The residueobtained was subjected to silica gel column chromatography, using ethylacetate as the eluent, to afford 1.26 g of the title compound as a palebrown, oily substance.

Nuclear magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.77 (3H, singlet);6.64 & 6.70 (each 1H, both singlets).

EXAMPLE 23 Sodium5-}6,7-dihydro-2-[α(1-imidazolyl)benzyl[-thianaphthene}carboxylatedehydrate

Using the same procedure as described in Example 19, 0.15 g of methyl6,7-dihydro-2-[(1-imidazolyl)benzyl]thianaphthene-5-carboxylate(prepared as described in Example 22) was hydrolyzed with sodiumhydroxide, and the product was reprecipitated from a mixture of ethanoland diethyl ether, to afford 0.09 g of the title compound as acolorless, amorphous powder.

Infrared Absorption Spectrum (Nujol mull) ν_(max) cm⁻¹ ; 1550.

Elemental analysis:

Calculated for C₁₉ H₁₅ N₂ O₂ SNa.2H₂ O: C, 57.86%; H, 4.86%; N, 7.10%;S, 8.13%. Found: C, 57.49%; H, 4.11%; N, 6.89%; 3, 8.01%.

EXAMPLE 24 Methyl4,5,6,7-tetrahydro-2-[(3-pyridyl)methyl]thianaphthene-5-carboxylate24(a) Methyl6,7-dihydro-2-[(hydroxy)(3-pyridyl)methyl]thianaphthene-5-carboxylate

12 ml of a 15% w/v solution of butyllithium in hexane was added to asolution of 2.17 ml of 3-bromopyridine in 40 ml of diethyl ether at -78°C. under an atmosphere of nitrogen, and the mixture was stirred for 30minutes. A solution of 2.5 g of methyl2-formyl-6,7-dihydrothianaphthene-5-carboxylate in a mixture of 20 mleach of diethyl ether and tetrahydrofuran was added dropwise thereto.The reaction mixture was then warmed up to room temperature over aperiod of about one hour and poured into an aqueous solution of ammoniumchloride. It was then extracted with ethyl acetate. The extract waswashed with an aqueous solution of sodium chloride, dried over anhydroussodium sulfate and concentrated by evaporation under reduced pressure.The residue was subjected to silica gel column chromatography, usingethyl acetate as the eluent, to afford 1.61 g of the title compound as apale brown, oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.74 (3H, singlet);5.95 (1H, singlet). 6.67 (1H, singlet).

24(b) Methyl4,5,6,7-tetrahydro-2-[(3-pyridyl)methylthianaphthene-5-carboxylate

1.0 g of methyl6,7-dihydro-2-[(hydroxy)(3-pyridyl)methyl]thianaphthene-5-carboxylate[prepared as described in step (a) above] was catalytically reduced inthe presence of 2 g of 10% w/w palladium-on-carbon and of 3.48 ml of a1N solution of hydrochloric acid under an atomsphere of hydrogen. Thereaction mixture was then treated as described in Example 20. Theproduct was subjected to silica gel column chromatography, using a 1:2by volume mixture of hexane and ethyl acetate as the eluent, to afford0.12 g of the title compound as a pale brown, oily substance.

Nuclear magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.71 (3H, singlet);4.03 (2H, singlet); 6.47 (1H, singlet).

EXAMPLE 255-}2-[(3-pyridyl)methyl]-4,5,6,7-tetrahydrothianaphthene}carboxylic acidhydrochloride 1/4 hydrate

A solution of 0.12 g of methyl4,5,6,7-tetrahydro-2-[(3-pyridyl)methyl]thianaphthene-5-carboxylate[prepared as described in Example 24(a)] in a mixture of 2 ml each ofconcentrated hydrochloric acid and glacial acetic acid was heated underreflux for 10 hours. At the end of this time, the reaction mixture wasevaporated to dryness. The residue obtained was recrystallized from amixture of ethanol and diethyl ether, to afford 0.10 g of the titlecompound as colorless needles, melting at 227°-229° C.

Elemental analysis: Calculated for C₁₅ H₁₅ NO₂.HCl.1/4 H₂ O: C, 57.32%;H, 5.29%; N, 4.46%; S, 10.20%, Cl, 11.28%.

Found: C, 57.70%; H, 5.38%; N, 4.23%; S, 10.03%; Cl, 11.50%.

EXAMPLE 26 Methyl2-[2-(1-imidazolyl)ethyl]-6,7-dihydrothianaphthene-5-carboxylate

A solution of 200 mg of imidazole in 4 ml of dimethylformamide was addeddropwise to a suspension of 70 mg of sodium hydride (as a 55% w/wsuspension in mineral oil) in 2 ml of dimethylformamide at roomtemperature under an atomsphere of nitrogen. After 15 minutes, asolution of 0.19 g of methyl2-(2-methanesulfonyloxyethyl)-6,7-dihydrothianaphthene-5-carboxylate in4 ml of dimethylformamide was added dropwise thereto, and the mixturewas stirred at room temperature for one hour. At the end of this time,the reaction mixture was poured into ice-water and stirred for 1 hour.It was then extracted with ethyl acetate. The extract was washed wellwith water, dried over anhydrous sodium sulfate, filtered andconcentrated by evaporation under reduced pressure. The resultingresidue was subjected to silica gel column chromatography, using a10:1:1 by volume mixture of ethyl acetate, ethanol and triethylamine asthe eluent, to afford 90 mg of the title compound as a pale brown, oilysubstance.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.80 (3H, singlet);6.56 (1H, singlet).

EXAMPLE 27 Sodium 5-2-[2-(1-imidazolyl)ethyl]-6,7-dihydrothianaphthenecarboxylate

Using the same procedure as described in Example 19, 30 g mg of methyl2-[2-(1-imidazolyl)ethyl]-6,7-dihydrothianaphthene-5-carboxylate(prepared as described in Example 26) were hydrolyzed with sodiumhydroxide, and the product was recrystallized from a mixture of ethanoland diethyl ether, to afford 20 mg of the title compound as colorlessneedles, melting at 180°-183° C. (with decomposition).

EXAMPLE 284,5,6,7-Tetrahydro-2-[(1-imidazolyl)methyl]-5-methoxycarbonylmethylidenethianaphthene

Using the same procedure as described in Example 18, 0.29 g of the titlecompound was obtained as a pale brown, oily substance from 1.24 g of4,5,6,7-tetrahydro-2-hydroxylmethyl-5-methoxycarbonylmethylidenethianaphthene.Nuclear magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.71 (3H, singlet);5.16 (2H, singlet); 6.24 (1H, singlet); 6.70 (1H, singlet).

EXAMPLE 29 Sodium salt of[2-(1-imidazolyl)methyl]-5-carboxymethylidenethianaphthene

Using the same procedure as described in Example 19, 0.29 g of4,5,6,7-tetrahydro-2-[(1-imidazolyl)methyl]-5-methoxycarbonylmethylidenethianaphthene(prepared as described in Example 28) was hydrolyzed with sodiumhydroxide, and the product was recrystallized from a mixture of ethanoland diethyl ether, to afford 0.20 g of the title compound as a paleyellow powder, melting at 233°-235° C. (with decomposition).

EXAMPLE 30 Methyl2-[1-(1-imidazolyl)-2,2-dimethylpropyl]-6,7-dihydrothianaphthene-5-carboxylate

Using the same procedure as described in Example 22, 0.95 g of the titlecompound was obtained as a pale brown oily substance from 1.05 g ofmethyl2-(2,2-dimethyl-1-hydroxypropyl)-6,7-dihydrothianaphthene-5-carboxylate.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 1.06 (9H, singlet);3.80 (3H, singlet); 6.91 (1H, singlet).

EXAMPLE 31 Sodium5-}6,7-dihydro-2-[1-(1-imidazolyl)-2,2-dimethylpropyl]thianaphthene}carboxylate3/2 hydrate

Using the same procedure as described in Example 19, 0.95 g of methyl2-[1-(1-imidazolyl)-2,2-dimethylpropyl]-6,7-dihydrothianaphthene-5-carboxylatewas hydrolyzed, and the product was reprecipitated from a mixture ofmethanol and diethyl ether, to afford 0.71 g of the title compound as acolorless, amorphous powder,

Infrared Absorption Spectrum (Nujol mull) ν_(max) cm⁻¹ ; 1620, 1560.

Elemental analysis: Calculated for C₁₇ H₁₉ N₂ O₂ SNa.3/2 H₂ O: C,55.88%, H, 6.07%; N, 7.67%; S, 8.77%. Found: C, 55.56%; H, 5.76%; N,7.24%; S, 8.62%.

EXAMPLE 32 Methyl6,7-dihydro-2-[(cyclohexyl)(1-imidazolyl)methyl]thianaphthene-5-carboxylate

Using the same procedure as described in Example 22, 0.41 g of the titlecompound was obtained as a pale brown, oily substance from 1.42 g ofmethyl6,7-dihydro-2-[(cyclohexyl)(hydroxy)methyl]thianaphthene-5-carboxylate(prepared as described in Preparation 25).

Nuclear magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.77 (3H, singlet).

EXAMPLE 33 Sodium5-(6,7-dihydro-2-[(cyclohexyl)(1-imidazolyl)methyl]thianaphthene}carboxylate3/2 hydrate

Using the same produce as described in Example 19, 0.41 g of methyl6,7-dihydro-2-[(cyclohexyl)(1-imidazolyl)methyl]thianaphthene-5-carboxylate(prepared as described in Example 32) was hydrolyzed, and the productwas reprecipitated from a mixture of methanol and diethyl ether, toafford 0.25 g of the title compound as a colorless, amorphous powder.

Infrared Absorption Spectrum (Nujol mull) ν_(max) cm⁻¹ ; 1625, 1560.

Elemental analysis: Calculated for C₁₉ H₂₁ N₂ O₂ SNa.3/2H₂ O: C, 58.30%;H, 6.18%; N, 7.16%; S, 8.19%. Found: C, 58.39%; H, 6.19%; N, 6.92%; S,8.31%.

EXAMPLE 34 Methyl4,5,6,7-tetrahydro-2-[(cyclohexyl)(1-imidazolyl)methyl[thianaphthene-5-carboxylate

Using the same procedure as described in Example 22, 0.39 g of the titlecompound was obtained as a pale brown, oily substance from 0.52 g ofmethyl4,5,6,7-tetrahydro-2-[(cyclohexyl)(hydroxy)methyl]thianaphthenecarboxylate[prepared in a manner similar to that described in Example 24(a), butemploying methyl 2-formyl-6,7-dihydrothianaphthene-5-carboxylate as thestarting material].

Nuclear magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.70 (3H, singlet);6.63 (1H, singlet).

EXAMPLE 355-{4,5,6,7-Tetrahydro-2-[(cyclohexyl)(1-imidazolyl)methyl]thianaphthenecarboxylic acid hydrochloride hydrate

Using the same procedure as described in Example 21, 0.38 g of methyl4,5,6,7-tetrahydro-2-[(cyclohexyl)-(1-imidazolyl)methyl]thianaphthene-5-carboxylate was hydrolyzed, and the product wasrecrystallized from a mixture of methanol and diethyl ether, to afford0.19 g of the title compound as colorless needless, melting at 202°-204°C.

Elemental analysis: Calculated for C₁₉ H₂₄ N₂ O₂ S.HCl.H₂ O: C, 57.20%;H, 6.82%; N, 7.02%; S, 8.05%; Cl, 8.89%. Found: C, 56.77%; H, 6.69%; N,7.45%; S, 8.25%; Cl, 9.10%. EXAMPLE 36 Methyl5-(1-imidazolyl)methyl-4,5,6,7-tetrahydrothianaphthene-2-carboxylate

A solution of 0.35 g of imidazole in 10 ml of dimethylformamide wasadded dropwise at room temperature to a suspension of 0.12 g of sodiumhydride (as a 55% w/w suspension in mineral oil) in 10 ml ofdimethylformamide under an atmosphere of nitrogen. After 30 minutes, asolution of 0.78 g of methyl5-methanesulfonyloxymethyl-4,5,6,7-tetrahydrothianaphthene-2-carboxylate(prepared as described in Preparation 46) in 20 ml of dimethylformamidewas added dropwise thereto, and the mixture was allowed to react for 2hours whilst heating at 50° C. At the end of this time, the reactionmixture was poured into ice-water containing 0.17 ml of glacial aceticacid. The mixture was then adjusted to a pH value of 8 by the additionof an aqueous solution of sodium bicarbonate and extracted with ethylacetate. The extract was washed with an aqueous solution of sodiumchloride, dried over anhydrous sodium sulfate, filtered and concentratedby evaporation under reduced pressure. The resulting residue wassubjected to silica gel column chromatography, eluted with a 20:1:1 byvolume mixture of ethyl acetate, ethanol and triethylamine), to afford0.49 g of the title compound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.85 (3H, singlet);3.95 (2H, doublet, J =6.0 Hz); 6.85-7.6 (4H, multiplet).

EXAMPLE 372-[5-(1-Imidazolyl)methyl-4,5,6,7-tetrahydrothianaphthene]carboxylicacid hydrochloride

0.47 g of methyl5-(1-imidazolyl-methyl)-4,5,6,7-tetrahydrothianaphthene-2-carboxylate(prepared as described in Example 36) was dissolved in a mixture of 5 mleach of glacial acetic acid and concentrated hydrochloric acid, and themixture was heated under reflux for 6 hours. At the end of this time,the reaction mixture was evaporated to dryness under reduced pressure,and the resulting residue was reprecipitated from a mixture of isopropylalcohol and diethyl ether, to afford 0.47 g of the title compound as acolorless, amorphous powder.

Infrared Absorption Spectrum (KBr) ν_(max) cm⁻¹ ; 1680.

Elemental analysis: Calculated for C₁₃ H₁₄ N₂ O₂ S.HCl; C, 52.26%; H,5.06%; N, 9.38%; S, 10.73%; Cl, 11.87%. Found: C, 52.38%; H, 5.13%; N,9.16%; S, 10.55%; Cl, 12.01%.

EXAMPLE 38 Methyl5-(1-imidazolyl)methyl-6,7-dihydrothianaphthene-2-carboxylate

Using the same procedure as described in Example 36, 0.39 g of the titlecompound was obtained as an oily substance from 0.63 g of methyl5-methanesulfonyloxymethyl-6,7-dihydrothianaphthene-2-carboxylate(prepared as described in Preparation 34).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.88 (3H, singlet);4.63 (2H, singlet); 6.5-7.5 (5H, multiplet).

EXAMPLE 39 2-[5-(1-Imidazolyl)methyl-6,7-dihydrothianaphthene]carboxylicacid hydrochloride

Using the same procedure as described in Example 37, 0.27 g of the titlecompound was obtained as a colorless, amorphous powder from 0.31 g ofmethyl 5-(1-imidazolyl)methyl-6,7-dihydrothianaphthene-2-carboxylate(prepared as described in Example 38).

Infrared Absorption Spectrum (KBr) νhd maxcm⁻¹ ; 1690.

Elemental analysis: Calculated for C₁₃ H₁₂ N₂ O₂ S.HCl: C. 52.61%; H,4.42%; N, 9.44%; S, 10.80%; Cl, 11.95%. Found: C, 52.77%; H, 4.44%; N,9.20%; S, 11.03%; Cl, 12.01%.

EXAMPLE 40 Methyl6-(1-imidazolyl)methyl-4,5,6,7-tetrahydrothianaphthene-2-carboxylate

Using the same procedure as described in Example 36, 0.87 g of the titlecompound was obtained as a colorless, amorphous powder from 1.00 g ofmethyl6-methanesulfonyloxymethyl-4,5,6,7-tetrahydrothianaphthene-2-carboxylate(prepared as described in Preparation 38).

Nuclear magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.83 (3H, singlet);3.96 (2H, doublet, J =6.0Hz); 6.9-7.6 (4H, multiplet).

EXAMPLE 412-[6-(1-Imidazolyl)methyl-4,5,6,7-tetrahydrothianaphthene]carboxylicacid hydrochloride

Using the same procedure as described in Example 37, 0.51 g of the titlecompound was obtained as a colorless, amorphous powder from 0.74 g ofmethyl6-(1-imidazolyl)methyl-4,5,6,7-tetrahydrothianaphthene-2-carboxylate(prepared as described in Example 40).

Infrared Absorption Spectrum (KBr) ν_(max) cm⁻¹ ; 1685.

Elemental analysis: Calculated for C₁₃ H₁₄ N₂ O₂ S.HCl: C, 52.26%; H,5.06%; N, 9.38%; S, 10.73%; Cl, 11.87%. Found: C, 52.03%; H, 4.99%; N,9.53%; S, 10.71%; Cl, 11.72%.

EXAMPLE 42 Methyl6-(1-imidazolyl)methyl-4,5-dihydrothianaphthene-2-carboxylate

Using the same procedure as described in Example 36, 0.29 g of the titlecompound was obtained as a colorless, amorphous powder from 0.35 g ofmethyl 6-methanesulfonyloxymethyl-4,5-dihydrothianaphthene-2-carboxylate(prepared as described in Preparation 42).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.84 (3H, singlet);4.68 (2H, singlet); 6.5-7.6 (5H, multiplet).

EXAMPLE 43 2-[6-(1-Imidazolyl)methyl-4,5-dihydrothianaphthene]carboxylicacid hydrochloride

Using the same procedure as described in Example 37, 0.23 g of the titlecompound was obtained as a colorless, amorphous powder from 0.29 g ofmethyl 6-(1-imidazolyl)methyl-4,5-dihydrothianaphthene-2-carboxylate(prepared as described in Example 42).

Infrared Absorption Spectrum (KRr) ν_(max) cm⁻¹ ; 1690.

Elemental analysis: Calculated for C₁₃ H₁₂ N₂ O₂ S.HCl; C, 52.61%; H,4.42%; N, 9.44%; S, 10.80%; Cl, 11.95%. Found: C, 52.40%; H, 4.32%; N,9.60%; S, 10.59%; Cl, 11.88%.

EXAMPLE 44 Methyl5-[2-(1-imidazolyl)ethyl]-4,5,6,7-tetrahydrothianaphthene-2-carboxylate

Using the same procedure as described in Example 36, 1.28 g of the titlecompound was obtained as an oily substance from 1.50 g of methyl5-methanesulfonyloxymethyl-4,5,6,7-tetrahydrothianaphthene-2-carboxylate(prepared as described in Preparation 30).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.90 (3H, singlet);4.05 (2H, triplet, J=6.5 Hz); 6.9-7.6 (4H, multiplet).

EXAMPLE 452-(5-[2(1-Imidazolyl)ethyl]-4,5,6,7-tetrahydrothianaphthene}carboxylicacid hydrochloride

Using the same procedure as described in Example 37, 0.27 g of the titlecompound was obtained as a colorless, amorphous powder from 1.00 g ofmethyl5-[2-(1-imidazolyl)ethyl]-4,5,6,7-tetrahydrothianaphthene-2-carboxylate(prepared as described in Example 44).

Infrared Absorption Spectrum (KBr) ν_(max) cm⁻¹ ; 1690.

Elemental analysis: Calculated for C₁₄ H₁₆ N₂ O₂ S.HCl: C, 53.76%; H,5.48%; N, 8,96%; S, 10.25%; Cl, 11.33%. Found: C, 53.70%, H, 5.51%; N,9.13%; S, 10,39%; Cl, 11.27%.

PREPARATION 1 Methyl 4,5-dihydrothianaphthene-6-carboxylate

A solution of 20 g of 4,5,6,7-tetrahydro-7-ketothianaphthene indimethylformamide was added dropwise to a suspension of 6.31 g of sodiumhydride (as a 55% w/w suspension in mineral oil) in 100 ml ofdimethylformamide at room temperature, and the mixture was stirred for10 minutes. 33 ml of dimethyl carbonate was then added dropwise to thereaction mixture at 5° C., and the reaction mixture was stirred for 90minutes. It was then poured into a mixture of ice-water and 8.7 ml ofglacial acetic acid and filtered. The precipitate was collected, to give31.6 g of a crude product containing methyl4,5,6,7-tetrahydro-4-oxothianaphthene-6-carboxylate. A solution of thiscrude product in a mixture of 100 ml each of tetrahydrofuran andmethanol was cooled to -15° C., and 4.98 g of sodium borohydride wasadded thereto over a period of one hour. At the end of this time, thereaction mixture was concentrated by evaporation under reduced pressure.The residue was extracted with a mixture of a saturated aqueous solutionof sodium bicarbonate and ethyl acetate. The extract was washed 5-6times with water, dried over anhydrous sodium sulfate, filtered andconcentrated by evaporation under reduced pressure. The resultingresidue was dissolved in 500 ml of benzene, 2.5 g of p-toluenesulfonicacid monohydrate was added to the solution, and the mixture wassubjected to azeotropic distillation by heating for 30 minutes to removethe water produced. At the end of this time, the reaction mixture waspored into a saturated aqueous solution of sodium bicarbonate andextracted with ethyl acetate. The extract was washed with an aqueoussolution of sodium chloride, filtered and concentrated by evaporationunder reduced pressure. The product was subjected to silica gel columnchromatography, using a 1:1 by volume mixture of hexane and ethylacetate as the eluent, to afford 20.1 g of the title compound as an oilysubstance.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.80 (3H, singlet);6.86 & 7.29 (each 1H, both doublets, J = 5.0 Hz); 7.54 (1H, singlet).

PREPARATION 2 Methyl 2-formyl-4,5-dihydrothianaphthene-6-carboxylate

30 ml of a solution of 7.5 g of 4,5-dihydrothianaphthene-6-carboxylatewere added dropwise to a suspension of 10.3 g of aluminum chloride in 50ml of methylene chloride at -10° C. in an atmosphere of nitrogen. After10 minutes, a solution of 5.24 ml of dichloromethyl methyl ether in 30ml of methylene chloride was added dropwise thereto over a period of onehour, and the reaction mixture was concentrated by evaporation underreduced pressure. The residue was dissolved in ethyl acetate, and theresulting solution was then washed in turn with a saturated aqueoussolution of sodium bicarbonate and with an aqueous solution of sodiumchloride. It was then dried over anhydrous sodium sulfate, filtered andconcentrated by evaporation under reduced pressure. The residue wassubjected to silica gel column chromatography, using a 2:1 by volumemixture of hexane and ethyl acetate as the eluent, to afford 8.21 g ofthe title compound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.83 (3H, singlet);7.50 & 7.57 (each 1H, both singlets); 9.86 (1H, singlet).

PREPARATION 3 Methyl 2-benzoyl-4,5-dihydrothianaphthene-6-carboxylate

Using the same procedure as described in Preparation 2, 1.65 g of thetitle compound was obtained as an oily substance from 1.78 g of aluminumchloride, 1.17 ml of benzoyl chloride and 1.30 g of methyl4,5-dihydrothianaphthene-6-carboxylate.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.81 (3H, singlet).

PREPARATION 4 Methyl 4,5,6,7-tetrahydrothianaphthene-6-carboxylate

1.63 g of methyl 4,5-dihydrothianaphthene-6-carboxylate was subjected tocatalytic reduction in the presence of 1.6 g of 10% w/wpalladium-on-carbon in an atmosphere of hydrogen whilst shaking thesolution for 4 hours. At the end of this time, the reaction mixture wasevaporated to dryness under reduced pressure, and the residue wassubjected to silica gel column chromatography using a 10:1 by volumemixture of hexane and ethyl acetate as the eluent, to afford 1.31 g ofthe title compound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

3.73 (3H, singlet); 6.75 & 7.08 (each 2H, both doublets, J =5.0 Hz).

PREPARATION 5 Methyl2-formyl-4,5,6,7-tetrahydrothianaphthene-6-carboxylate

Using the same procedure as described in Preparation 2, 0.3 g of thetitle compound was obtained as an oily substance from 0.50 g of methyl4,5,6,7-tetrahydro-thianaphthene-6-carboxylate (prepared as described inPreparation 4).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.73 (3H, singlet);7.45 (1H, singlet); 9.83 (1H, singlet).

PREPARATION 64,5,6,7-Tetrahydro-6-methoxycarbonylmethylidenethianaphthene

A solution of 9.57 g of 4,5,6,7-tetrahydro-7-ketothianaphthene in 30 mlof dimethylformamide was added dropwise to a suspension of 3.29 g ofsodium hydride (as a 55% w/w suspension in mineral oil) in 30 ml ofdimethylformamide in a nitrogen atomsphere. The mixture was cooled to 5°C., 16 ml of dimethyl carbonate was added dropwise thereto and themixture was stirred at room temperature for one hour. A solution of 6.6ml of methyl bromoacetate in 10 ml of dimethylformamide was then added,and the mixture was stirred at room temperature for one hour. At the endof this time, the reaction mixture was poured into ice-water andextracted with ethyl acetate. The extract was washed with an aqueoussolution of sodium chloride and concentrated by evaporation underreduced pressure. The residue was dissolved in ethyl acetate, and theresulting solution was washed in turn with water, with a saturatedaqueous solution of sodium bicarbonate and with an aqueous solution ofsodium chloride. The washed solution was then dried over anhydroussodium sulfate, filtered and concentrated by evaporation under reducedpressure. The residue was dissolved in a mixture of 200 ml each ofconcentrated hydrochloric acid and glacial acetic acid, and the solutionwas heated under reflux for 3 hours. The reaction mixture was thenevaporated to dryness under reduced pressure, the residue was dissolvedin 500 ml of methanol and 2 ml of concentrated sulfuric acid, and themixture was heated again under reflux for 2 hours. At the end of thistime, the product was concentrated by evaporation under reducedpressure. The residue was extracted with a mixture of a saturatedaqueous solution of sodium bicarbonate and ethyl acetate. The extractwas washed 5-6 times with water, dried over anhydrous sodium sulfate,filtered and concentrated by evaporation under reduced pressure. Theresulting residue was subjected to silica gel column chromatography,using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent,to afford 10.13 g of4,5,6,7-tetrahydro-7-keto-6-methoxycarbonylmethylthianaphthene as anoily substance.

2.0 g of sodium borohydride were added to a solution of 10.13 g of theketone thus prepared in 200 ml of methanol, and the mixture was stirredat room temperature for 30 minutes. At the end of this time, thereaction mixture was concentrated by evaporation under reduced pressure.The residue was extracted with a mixture of a saturated aqueous solutionof sodium bicarbonate and ethyl acetate. The extract was washed 5-6times with water, dried over anhydrous sodium sulfate, filtered andconcentrated by evaporation under reduced pressure. The resultingresidue was acetylated with 20 ml of acetic anhydride in 40 ml ofpyridine. 0.7 g of p-toluenesulfonic acid monohydrate was added to asolution of the acetylated product in 250 ml of toluene, and the mixturewas heated under reflux for 30 minutes. At the end of this time, theproduct the poured into a saturated aqueous solution of sodiumbicarbonate and extracted with ethyl acetate. The extract was washedwith an aqueous solution of sodium chloride, filtered and concentratedby evaporation under reduced pressure. The residue was subjected tosilica gel column chromatography, using a 5:1 by volume mixture ofhexane and ethyl acetate as eluent, to afford 5.50 g of the titlecompound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.65 (3H, singlet);6.34 (1H, singlet).

PREPARATION 72-Formyl-4,5,6,7-tetrahydro-6-methoxycarbonylmethylidenethianaphthene

Using the same procedure as described in preparation 2, 1.50 g of thetitle compound was obtained as an oily substance from 2.50 g of4,5,6,7-tetrahydro-6-methoxycarbonylmethylidenethianaphthene (preparedas described in Preparation 6).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.72 (3H, singlet);6.33 (1H, singlet); 7.40 (1H, singlet);

9.81 (1H, singlet).

PREPARATION 8 Ethyl 6-(4,5-dihydrothianaphthene)carboxylate

8(a) A solution of 57 ml of tin tetrachloride in 600 ml of methylenechloride was cooled at -35° C., and then a solution of 60 g of ethyl4-(3-thienyl)butyrate in 600 ml of methylene chloride was added dropwiseunder a nitrogen atmosphere over a period of one hour. 20 minutes afterthe dropwise addition was complete, a solution of 35 ml ofdichloromethyl methyl ether in 600 ml of methylene chloride was addeddropwise to the resulting mixture over a period of one hour, whilemaintaining the mixture at a temperature of -35° C., and stirring wascontained for a further one hour. At the end of this time, the reactionmixture was treated in a conventional manner to give a crude syrupysubstances containing ethyl 4-[3-(2-formyl)thienyl]butyrate.

8(b) 18.5 ml of ethanol were added dropwise to a suspension of 13.86 gof sodium hydride (as a 55% w//w suspension in mineral oil) in 500 ml oftoluene under a nitrogen atomsphere at room temperature, and theresulting mixture was then heated to 80° C. A solution of the syrupysubstance [obtained as described in step (a) above] in 250 ml of toluenewas added all at once and the resulting mixture was allowed to cool atroom temperature.

When the reaction mixture was cool, it was treated in a conventionalmanner to give a syrupy substance, which was then distilled underreduced pressure to give 32.80 g of the title compound boiling at125°-128° C./2mmHg (266 Pa).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 1.31 (triplet, 7 Hz);4.24 (7 Hz, quartet); 6.89 & 7.29 (each doublet, 5 Hz); 7.54 (singlet).

PREPARATION 9 Methyl 6,7-dihydrothianaphthene-5-carboxylate

A solution of 20 g of 4,5,6,7-tetrahydro-4-ketothianaphthene indimethylformamide was added dropwise at room temperature to a suspensionof 6.31 g of sodium hydride (as a 55% w/w suspension in mineral oil) in100 ml of dimethylformamide, and the mixture was stirred for 10 minutes.33 ml of dimethyl carbonate were added dropwise at 5° C. to the abovereaction mixture, and the mixture was then stirred for 90 minutes. Thereaction mixture was then poured into a mixture of ice-water and 8.7 mlof glacial acetic acid, and the mixture was filtered to obtain 31.6 g ofa crude product containing methyl4,5,6,7-tetrahydro-4-ketothianaphthene-5-carboxylate. A solution of thecrude product in a mixture of 100 ml each of tetrahydrofuran andmethanol was cooled to -15° C., and 4.98 g of sodium borohydride wasadded thereto over a period of one hour. At the end of this time, thereaction mixture was concentrated by evaporation under reduced pressure.The residue was dissolved in ethyl acetate, and the resulting solutionwas washed with an aqueous solution of sodium chloride, dried overanhydrous sodium sulfate, filtered and then concentrated by evaporationunder reduced pressure. The residue was then dissolved in 500 ml ofbenzene. 2.5 g of p-toluenesulfonic acid monohydrate was added thereto,and the mixture was subjected to azeotropic distillation by heating for30 minutes to remove the water produced. At the end of this time, thereaction mixture was poured into a saturated aqueous solution of sodiumbicarbonate and extracted with ethyl acetate. The extract was washedwith an aqueous solution of sodium chloride, dried over anhydrous sodiumsulfate, filtered and then concentrated by evaporation under reducedpressure. The resulting residue was subjected to silica gel columnchromatography, using a 1:1 by volume mixture of hexane and ethylacetate as the eluent, to afford 20.1 g of the title compound as an oilysubstance.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.78 (3H, singlet);6.93 & 7.08 (each 1H, both doublets, J=5.0 Hz); 7.52 (1H, singlet).

PREPARATION 10 Methyl 2-formyl-6,7-dihydrothianaphthene-5-carboxylate

A solution of 7.5 g of methyl 6,7-dihydrothianaphthene-5-carboxylate(prepared as described in Preparation 9) in 30 ml of methylene chloridewas added dropwise at -10° C. to a suspension of 10.3 g of aluminumchloride in 50 ml of methylene chloride under an atmosphere of nitrogen.After 10 minutes, a solution of 5.24 ml of dichloromethyl methyl etherin 30 ml of methylene chloride was added dropwise thereto over a periodof one hour, and the reaction mixture was poured into ice-water andstirred for 1 hour. The mixture was then extracted with methylenechloride. The extract was washed with an aqueous solution of sodiumchloride, dried over anhydrous sodium sulfate, filtered and concentratedby evaporation under reduced pressure. The resulting residue wasrecrystallized from a mixture of ethyl acetate and hexane, to afford8.21 g of the title compound as pale red needles, melting at 125°-127°C.

PREPARATION 11 Methyl 2-acetyl-6,7-dihydrothianaphthene-5-carboxylate

A solution of 2.0 g of methyl 6,7-dihydrothianaphthene-5-carboxylate(preferred as described in Preparation 9) in 30 ml of methylene chloridewas added dropwise at -10° C. to a suspension of 2.75 g of aluminumchloride in 30 ml of methylene chloride. After 10 minutes, a solution of1.10 ml of acetyl chloride in 10 ml of methylene chloride was addedthereto over a period of 30 minutes. At the end of this time, thereaction mixture was treated as described in Preparation 10 from pouringinto ice-water to concentration, and the residue obtained was subjectedto silica gel column chromatography, using a 3:1 by volume mixture ofhexane and ethyl acetate as the eluent. The product was thenrecrystallized from a mixture of ethyl acetate and hexane, to afford2.25 g of the title compound as pale yellow needles, melting at116°-118° C.

PREPARATION 12 Methyl 2-Benzoyl-6,7-dihydrothianaphthene-5-carboxylate

Using the same procedure as described in Preparation 11. 1.78 g ofaluminum chloride, 1.17 ml of benzoyl chloride and 1.30 g of methyl6,7-dihydrothianaphthene-5-carboxylate (prepared as described inPreparation 9) were reacted together. The reaction mixture was treatedas described in Preparation 10 from pouring into ice-water toconcentration, and the resulting residue was subjected to silica gelcolumn chromatography, using a 4:1 by volume mixture of hexane and ethylacetate as the eluent. The product was then recrystallized from amixture of ethyl acetate and hexane, to afford 1.65 g of the titlecompound as colorless needles, melting at 99°-101° C.

PREPARATION 13 Methyl6,7-dihydro-2-(2-methoxyvinyl)thianaphthene-5-carboxylate

A solution of 3.48 g of methyl2-formyl-6,7-dihydrothianaphthene-5-carboxylate (prepared as describedin Preparation 10) in 30 ml of tetrahydrofuran was added dropwise to anethereal solution of an ylide prepared from 13.42 g ofmethoxymethyltriphenylphosphoridene chloride and 19.0 ml of a 15% w/vhexane solution of butyllithium under an atmosphere of nitrogen. At theend of this time, the reaction mixture was poured into ice-water, andextracted with diethyl ether. The extract was washed with an aqueoussolution of sodium chloride and dried over anhydrous sodium sulfate, andthe solvent was removed by evaporation under reduced pressure. Theresidue was subjected to silica gel column chromatography, using amixture of hexane and ethyl acetate as the eluent, to afford 1.0 g ofthe title compound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3,60 & 3.73 (6H, eachsinglet).

PREPARATION 142-(5-Methoxycarbonyl-6,7-dihydrothianaphthenyl)acetaldehyde

A solution of 1.0 g of methyl6,7-dihydro-2-(2-methoxyvinyl)thianaphthene-5-carboxylate (prepared asdescribed in Preparation 13) in a mixture of 30 ml of a 1% w/vhydrochloric acid and 60 ml of acetone was heated under reflux for 9hours. The solvent was removed from the reaction mixture under reducedpressure. The residue was dissolved in ethyl acetate, and the resultingsolution was washed in turn with a saturated aqueous solution of sodiumbicarbonate and with a saturated aqueous solution of sodium chloride. Itwas then dried over anhydrous sodium sulfate, and the solvent wasremoved by evaporation under reduced pressure. The residue was subjectedto silica gel column chromatography, using a 2:1 by volume mixture ofhexane and ethyl acetate as the eluent, to afford 0.24 g of the titlecompound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 9.90 (1H).

PREPARATION 15 Methyl6,7-dihydro-2-(2-hydroxyethyl)thianaphthene-5-carboxylate

42 mg of sodium borohydride were added to a solution of 0.24 g of2-(5-methoxycarbonyl-6,7-dihydrothianaphthenyl)acetaldehyde (prepared asdescribed in Preparation 14) in a mixture of 10 ml each of methanol andtetrahydrofuran. At the end of this time, the reaction mixture wasconcentrated by evaporation under reduced pressure. The residue wasdissolved in ethyl acetate, and the resulting solution was washed withan aqueous solution of sodium chloride, dried over anhydrous sodiumsulfate, filtered and then concentrated by evaporation under reducedpressure. The resulting residue was subjected to silica gel columnchromatography, using a 3:2 by volume mixture of hexane and ethylacetate as the eluent, to afford 0.17 g of the title compound as an oilysubstance.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.80 (3H, singlet);6.73 (1H, singlet); 7.45 (1H, singlet).

PREPARATION 16 Methyl2-(2-methanesulfonyloxyethyl)-6,7-dihydrothianaphthene-5-carboxylate

A solution of 0.08 ml of methanesulfonyl chloride in 3 ml of diethylether was added to a solution of 0.17 g of methyl6,7-dihydro-2-(2-hydroxyethyl)thianaphthene-5-carboxylate (prepared asdescribed in Preparation 15) in a mixture of 5 ml of diethyl ether and0.30 ml of triethylamine, and the mixture was stirred at roomtemperature for 30 minutes. At the end of this time, the reactionmixture was poured into ice-water, and the mixture was extracted withdiethyl ether. The extract was washed in turn with a saturated aqueoussolution of sodium bicarbonate and with an aqueous solution of sodiumchloride. It was then dried over anhydrous sodium sulfate, filtered andconcentrated by evaporation under reduced pressure. The resultingresidue was subjected to silica gel column chromatography, using a 2:1by volume mixture of hexane and ethyl acetate as the eluent, to afford0.19 g of the title compound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm; 2.97 (3H, singlet);3.78 ((3H, singlet).

PREPARATION 174,5,6,7-Tetrahydro-4-keto-5-(methoxycarbonylmethyl)thianaphthene

A solution of 9.57 g of 4,5,6,7-tetrahydro-4-ketothianaphthene in 30 mlof dimethylformamide was added dropwise to a suspension of 3.29 g ofsodium hydride (as a 55% w/w suspension in mineral oil) in 30 ml ofdimethylformamide under an atomsphere of nitrogen. The mixture wascooled to 5° C. 16 ml of dimethyl carbonate was added thereto, and themixture was stirred at room temperature for one hour. A solution of 6.6ml of methyl bromoacetate in 10 ml of dimethylformamide was addeddropwise thereto, and the mixture was stirred for one hour. At the endof this time, the reaction mixture was poured into ice-water andextracted with ethyl acetate. The extract was washed with a saturatedaqueous solution of sodium chloride and dried over anhydrous sodiumsulfate. The solvent was then removed by evaporation under reducedpressure. The residue was dissolved in a mixture of 200 ml each ofconcentrated aqueous hydrochloric acid and glacial acetic acid, and thesolution was heated under reflux for 3 hours. The reaction mixture wasthen evaporated to dryness under reduced pressure, and the residue wasdissolved in a mixture of 500 ml of methanol and 2 ml of concentratedsulfuric acid. The solution was heated under reflux for 2 hours. At theend of this time, the solvent was removed by evaporation under reducedpressure, and the residue was dissolved in ethyl acetate. The solutionwas washed in turn with water, with a saturated aqueous sodiumbicarbonate and with a saturated aqueous solution of sodium chloride anddried over anhydrous sodium sulfate. The solvent was then removed byevaporation under reduced pressure. The residue was subjected to silicagel column chromatography, using a 2:1 by volume mixture of hexane andethyl acetate as the eluent, to afford 10.13 g of the title compound asan oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.72 (3H, singlet);7.06 & 7.38 (each 1H, both doublets, J=6.0 Hz.)

PREPARATION 184,5,6,7-Tetrahydro-5-(methoxycarbonylmethylidene)thianaphthene

2.0 g of sodium borohydride was added to a solution of 10.13 g of4,5,6,7-tetrahydro-4-keto-5-(methoxycarbonylmethyl)thianaphthene(prepared as described in Preparation 17) in 200 ml of methanol, and themixture was stirred at room temperature for 30 minutes. At the end ofthis time, the reaction mixture was concentrated by evaporation underreduced pressure. The residue was dissolved in ethyl acetate, and theresulting solution was washed with an aqueous solution of sodiumchloride, dried over anhydrous sodium sulfate, filtered and thenconcentrated by evaporation under reduced pressure. The residue wasdried thoroughly under reduced pressure and then acetylated with 20 mlof acetic anhydride in 40 ml of pyridine. At the end of this time, thereaction mixture was concentrated by evaporation under reduced pressure.The resulting residue was dissolved in ethyl acetate, and the solutionwas washed in turn with water, with a saturated aqueous solution ofsodium bicarbonate and with a saturated aqueous solution of sodiumchloride. It was then filtered and concentrated by evaporation underreduced pressure. The resulting residue was dissolved in 250 ml oftoluene, and the solution was heated under reflux in the presence of 0.7g of p-toluenesulfonic acid monohydrate for 30 minutes. At the end ofthis time, the reaction mixture was concentrated by evaporation underreduced pressure. The residue was dissolved in ethyl acetate, and theresulting solution was washed with an aqueous solution of sodiumchloride, dried over anhydrous sodium sulfate, filtered and thenconcentrated by evaporation under reduced pressure. The resultingresidue was subjected to silica gel column chromatography, using a 5:1by volume mixture of hexane and ethyl acetate, to afford 5.50 g of thetitle compound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.17 (2H, singlet);3.67 (3H, singlet); 6.31 (1H, singlet).

PREPARATION 192-Formyl-4,5,6,7-tetrahydro-5-(methoxycarbonylmethylidene)thianaphthene

Following the same procedure as described in Preparation 10, 1.50 g ofthe title compound was obtained as an oily substance from 2.50 g of4,5,6,7-tetrahydro-5-(methoxycarbonylmethylidene)thianaphthene (preparedas described in Preparation 17).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δppm: 3.70 (3H, singlet);6.29 (1H, singlet); 7.40 (1H, singlet); 9.75(1H, singlet).

PREPARATION 204,5,6,7-Tetrahydro-2-hydroxymethyl-5-(methoxycarbonylmethylidene)thianaphthene

0.26 g of sodium borohydride was added to a solution of 1.47 g of2-formyl-4,5,6,7-tetrahydro-5-(methoxycarbonylmethylidene)thianaphthene(prepared as described in Preparation 19) in a mixture of 30 ml each ofmethanol and tetrahydrofuran. At the end of this time, the reactionmixture was concentrated by evaporation under reduced pressure. Theresidue was dissolved in ethyl acetate, and the resulting solution waswashed with an aqueous solution of sodium chloride, dried over anhydroussodium sulfate, filtered and then concentrated by evaporation underreduced pressure. The residue was subjected to silica gel columnchromatography, using a 3:2 by volume mixture of hexane and ethylacetate, to afford 1.24 g of the title compound as an oily substance.

Nuclear magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.69 (3H, singlet);6.24 (1H, singlet); 6.67 (1H, singlet).

PREPARATION 21 Methyl2-trimethylacetyl-6,7-dihydrothianaphthene-5-carboxylate

Using the same procedure as described in Preparation 11, 1.47 g of thetitle compound was obtained as an oily substance using 3.8 g of aluminumchloride, 3.0 g of methyl 6,7-dihydrothianaphthene-5-carboxylate(prepared as described in Preparation 9) and 2.7 ml of pivaloylchloride.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 1.40 (9H, singlet);3.82 (3H, singlet); 7.62 (1H, singlet).

PREPARATION 22 Methyl2-(2,2-dimethyl-1-hydroxyethyl)-6,7-dihydrothianaphthene-5-carboxylate

Using the same procedure as described in Preparation 15, 1.05 g of thetitle compound was obtained as an oily substance from 1.47 g of methyl2-trimethlacetyl-6,7-dihydrothianaphthene-5-carboxylate (prepared asdescribed in Preparation 14).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 0.95 (9H, singlet);3.75 (3H, singlet); 6.65 (1H, singlet).

PREPARATION 23 Methyl2-cyclohexylcarbonyl-6,7-dihydrothianaphthene-5-carboxylate

Using the same procedure as described in Preparation 11, 279 g of thetitle compound was obtained as an oily substance using 2.56 g ofaluminum chloride, 2.0 g of methyl6,7-dihydrothianaphthene-5-carboxylate (prepared as described inPreparation 9) and 1.93 ml of cyclohexanecarbonyl chloride.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.83 (3H, singlet);7.52 (1H, singlet); 7.58 (1H, singlet).

PREPARATION 24 Methyl2-cyclohexylcarbonyl-5-methoxycarbonyl-4,5,6,7-tetrahydrothianaphthene-5-carboxylate

1.07 g of methyl2-cyclohexylcarbonyl-6,7-dihydrothianaphthene-5-carboxylate (prepared asdescribed in Preparation 23) in methanol was catalytically reduced over1.0 g of 10% w/v palladium-on-carbon in the presence of catalyticamounts of acetic acid and in an atmosphere of hydrogen. The reactionmixture was then adjusted to a pH value of 8 by the addition of anaqueous solution of sodium bicarbonate. The resulting solution wasfiltered, and the filtrate was concentrated by evaporation under reducedpressure. The residue was dissolved in ethyl acetate, and the solutionwas dried over anhydrous sodium sulfate, filtered and concentrated byevaporation under reduced pressure, to afford 0.58 g of the titlecompound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.75 (1H, singlet);7.43 (1H, singlet).

PREPARATION 25 Methyl6,7-dihydro-2-[(cyclohexyl)(hydroxy)methyl]thianaphthene-5-carboxylate

Using the same procedure as described in Preparation 15, 1.42 g of thetitle compound was obtained as an oily substance from 1.72 g of methyl2-cyclohexylcarbonyl-6,7-dihydrothianaphthene-5-carboxylate (prepared asdescribed in Preparation 23).

PREPARATION 26 Methyl4,5,6,7-tetrahydro-2-[(cyclohexyl)(hydroxy)methyl]thianaphthene-5-carboxylate

Using the same procedure described as in Preparation 24, 0.52 g of thetitle compound was obtained as an oily substance from 0.58 g of methyl6,7-dihydro-2-[(cyclohexyl)(hydroxy)methyl]thianaphthene-5-carboxylate(prepared as described in Preparation 25).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.73 (3H, singlet);6.60 (1H, singlet).

PREPARATION 27 5Hydroxymethyl-4,5,6,7-tetrahydrothianaphthene

A solution of 3.20 g of methyl4,5,6,7-tetrahydrothianaphthene-5-carboxylate in 35 ml of diethyl etherwas added dropwise to a suspension of 0.62 g of lithium aluminum hydridein 30 ml of diethyl ether at below 10° C. After 10 minutes, sodiumsulfate decahydrate was added thereto and the mixture was stirred. Thereaction mixture was then filtered using a Celite 545 filter aid (Celiteis a trade mark), the filtrate was concentrated by evaporation underreduced pressure, and the residue was subjected to silica gel columnchromatography, using a 2:1 by volume mixture of hexane and ethylacetate as the eluent, to afford 2.59 g of the title compound as an oilysubstance.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.53 (2H, doublet);6.67 & 7.00 (each 1H, both doublets, J =6.0 Hz).

PREPARATION 285-Methanesulfonyloxymethyl-4,5,6,7-tetrahydrothianaphthene

A solution of 1.00 ml of methanesulfonyl chloride in 10 ml of methylenechloride was added dropwise to a solution of 1.09 g of5hydroxymethyl-4,5,6,7-tetrahydrothianaphthene (prepared as described inPreparation 27) in a mixture of 30 ml of methylene chloride and 2.71 mlof triethylamine with ice-water, whilst cooling. The mixture was thenstirred at room temperature for 1 hour. At the end of this time, thereaction mixture was poured into ice-water and extracted with methylenechloride. The extract was washed in turn with a saturated aqueoussolution of sodium bicarbonate and with an aqueous solution of sodiumchloride. It was then dried over anhydrous sodium sulfate, filtered andconcentrated by evaporation under reduced pressure. The resultingresidue was purified by column chromatography through silica gel, usinga 3:1 by volume mixture of hexane and ethyl acetate as the eluent, toafford 1.38 g of the title compound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 2.98 (3H, singlet);4.16 (2H, doublet, J=5.0 Hz); 6.72 & 7.05 (each 1H, both doublets, J=5.0 Hz).

PREPARATION 292-Formyl-5-methanesulfonyloxymethyl-4,5,6,7-tetrahydrothianaphthene

A solution of 1.18 g of5-methanesulfonyloxymethyl-4,5,6,7-tetrahydrothianaphthene (prepared asdescribed in Preparation 28) in 35 ml of methylene chloride was addeddropwise to a suspension of 0.96 g of anhydrous aluminum chloride in 40ml of methylene chloride at -30° C. under a nitrogen atmosphere. Asolution of 0.54 ml of dichloromethyl methyl ether in 20 ml of methylenechloride was then added, and the mixture was thereafter stirred at 0° C.for 2 hours. At the end of this time, the reaction mixture was pouredinto ice-water, stirred for 1 hour and extracted with methylenechloride. The extract was washed with an aqueous solution of sodiumchloride, dried over anhydrous sodium sulfate, filtered and concentratedby evaporation under reduced pressure. The resulting residue waspurified by column chromatography through silica gel, using a 1:1 byvolume mixture of hexane and ethyl acetate the as eluent, to afford 0.85g of the title compound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.06 (3H, singlet);4.24 (2H, doublet, J =5.0 Hz); 7.46 (1H, singlet); 9.85 (1H, singlet).

PREPARATION 30 Methyl5-methanesulfonyloxymethyl-4,5,6,7-tetrahydrothianaphthene-2-carboxylate

A solution of 0.40 g of sodium chlorite in 5 ml of water was addeddropwise to a solution of 0.80 g of2-formyl-5-methanesulfonyloxymethyl-4,5,6,7-tetrahydrothianaphthene(prepared as described in Preparation 29) and 1.77 g of sulfamic acid in48 ml of a 5:1 v/v mixture of dioxane and water at room temperature.When the dropwise addition was complete, the reaction mixture wasconcentrated by evaporation under reduced pressure. The residue wasdissolved in ethyl acetate, and the solution was washed with an aqueoussolution of sodium chloride, dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated by evaporation under reducedpressure and the resulting crude residue was dissolved in 150 ml ofmethanol. This solution was heated for 7 hours under reflux in thepresence of a catalytic amount of concentrated sulfuric acid. At the endof this time, the reaction mixture was concentrated by evaporation underreduced pressure, and the residue was dissolved in ethyl acetate. Theresulting solution was washed in turn with water, with an aqueoussolution of sodium bicarbonate and with an aqueous solution of sodiumchloride. It was then dried over anhydrous sodium sulfate, filtered andconcentrated by evaporation under reduced pressure. The resultingresidue was subjected to column chromatography through silica gel, usinga 3:2 by volume mixture of hexane and ethyl acetate as the eluent, toafford 0.78 g of the title compound as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.03 (3H, singlet);3.86 (3H, singlet); 4.22 (2H, doublet); 7.48 (1H, singlet).

PREPARATION 31 5-Hydroxymethyl-6,7-dihydrothianaphthene

Using the same procedure as described in Preparation 27, 1.65 g of thetitle compound was obtained as an oily substance from 2.07 g of methyl6,7-dihydrothianaphthene-5-carboxylate.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 4.19 (2H, doublet, J=6.0 Hz); 6.41 (1H, triplet, J =1.5 Hz); 6.81 & 7.03 (each 1H, bothdoublets, J =5.0 hz).

PREPARATION 32 5-Methanesulfonyloxymethyl-6,7-dihydrothianaphthene

Using the same procedure as described in Preparation 28, 1.07 g of thetitle compound was obtained as an oily substance from 1.14 g of5-hydroxymethyl-6,7-dihydrothianaphthene (prepared as described inPreparation 31).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.02 (3H, singlet);4.31 (2H, singlet); 6.45 (1H, triplet, J =1.5 Hz); 6.85 & 7.06 (each 1H,both doublets, J =5.0 Hz).

PREPARATION 332-Formyl-5-methanesulfonyloxymethyl-6,7-dihydrothianaphthene

Using the same procedure as described in Preparation 29, 082 g of thetitle compound was obtained as an oily substance from 0.99 g of5-methanesulfonyloxymethyl-6,7-dihydrothianaphthene (prepared asdescribed in Preparation 32).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.07 (3H, singlet);4.33 (2H, singlet); 6.46 (1H, triplet, J =1.5 Hz); 7.49 (1H, singlet);9.89 (1H, singlet).

PREPARATION 34 Methyl5-methanesulfonyloxymethyl-6,7-dihydrothianaphthene-2-carboxylate

Using the same procedure as described in Preparation 30, 0.69 g of thetitle compound was obtained as an oily substance from 0.75 g of2-formyl-5-methanesulfonyloxymethyl-6,7-dihydrothianaphthene (preparedas described in Preparation 33).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.02 (3H, singlet);3.88 (3H, singlet); 4.30 (2H, singlet); 6.43 (1H, triplet, J =1.5 Hz);7.50 (1H, singlet).

PREPARATION 35 6-Hydroxymethyl-4,5,6,7-tetrahydrothianaphthene

Using the same procedure as described in Preparation 27, 3.91 g of thetitle compound was obtained as an oily substance from 4.85 g of methyl4,5,6,7-tetrahydrothianaphthene-6-carboxylate (prepared as described inPreparation 4).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.57 (2H, doublet, J=6.0 Hz); 6.69 & 7.00 (each 1H, both doublets, J =5.0 Hz).

PREPARATION 366-Methanesulfonyloxymethyl-4,5,6,7-tetrahydrothianaphthene

Using the same procedure as described in Preparation 2, 4.28 g of thetitle compound was obtained as an oily substance from 3.50 g of6-hydroxymethyl-4,5,6,7-tetrahydrothianaphthene (prepared as describedin Preparation 35).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 2.98 (3H, singlet);4.17 (2H, doublet, J =6.0 Hz); 6.72 & 7.04 (each 1H, both doublets, J=5.0 Hz).

PREPARATION 372-Formyl-6-methanesulfonyloxymethyl-4,5,6,7-tetrahydrothianaphthene

Using the same procedure as described in Preparation 29, 2.92 g of thetitle compound was obtained as an oily substance from 4.11 g of6-methanesulfonyloxymethyl-4,5,6,7-tetrahydrothianaphthene (prepared asdescribed in Preparation 26).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.05 (3H, singlet);4.24 (2H, doublet, J =5.0 Hz); 7.46 (1H, singlet); 9.85 (1H, singlet).

PREPARATION 38 Methyl6-methanesulfonyloxymethyl-4,5,6,7-tetrahydrothianaphthene-2-carboxylate

Using the same procedure as described in Preparation 30, 2.19 g of thetitle compound was obtained as colorless needles melting at 188°-191° C.from 2.32 g of2-formyl-6-methanesulfonyloxymethyl-4,5,6,7-tetrahydrothianaphthene(prepared as described in Preparation 27).

Nuclear magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.05 (3H singlet);3.86 (3H, singlet); 4.20 (2H, doublet, J =5.0 Hz); 7.48 (1H, singlet).

PREPARATION 39 6-Hydroxymethyl-4,5-dihydrothianaphthene

Using the same procedure as described in Preparation 27, 1.19 g of thetitle compound was obtained as an oily substance from 1.64 g of methyl4,5-dihydrothianaphthene-6-carboxylate.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 4.22 (2H, doublet, J=6.0 Hz); 6.43 (1H, triplet, J =1.5 Hz); 6.71 & 7.02 (each 1H, bothdoublets, J =5.0 Hz).

PREPARATION 40 6-Methanesulfonyloxymethyl-4,5-dihydrothianaphthene

Using the same procedure as described in Preparation 28, 0.82 g of thetitle compound was obtained as an oily substance from 1.03 g of6-hydroxymethyl-4,5-dihydrothianaphthene (prepared as described inPreparation 39).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.01 (3H, singlet);4.33 (2H, singlet); 6.48 (1H, triplet, J =1.5 Hz); 6.81 & 7.06 (each 1H,both doublets, J =5.0 Hz).

PREPARATION 412-Formyl-6-methanesulfonyloxymethyl-4,5-dihydrothianaphthene

Using the same procedure as described in Preparation 29, 0.49 g of thetitle compound was obtained as an oily substance from 0.73 g of6-methanesulfonyloxymethyl-4,5-dihydrothianaphthene (prepared asdescribed in Preparation 40).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.05 (3H, singlet);4.31 (1H, singlet); 6.47 (1H, triplet, J =1.5 Hz); 7.50 (1H, singlet);9.88 (1H, singlet).

PREPARATION 42 Methyl6-methanesulfonyloxymethyl-4,5-dihydrothianaphthene-2-carboxylate

Using the same procedure as described in Preparation 30, 0.39 g of thetitle compound was obtained as an oily substance from 0.40 g of2-formyl-6-methanesulfonyloxymethyl-4,5-dihydrothianaphthene (preparedas described in Preparation 41).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.02 (3H, singlet);3.87 (3H, singlet); 4.29 (2H, singlet);

6.42 (1H, triplet, J =1.5 Hz); 7.49 (1H, singlet).

PREPARATION 43 5-(2-Hydroxyethyl)-4,5,6,7-tetrahydrothianaphthene

Using the same procedure as described in preparation 27, 3.75 g of thetitle compound was obtained as an oily substance from 4.50 g of5-methoxycarbonylmethyl-4,5,6,7-tetrahydrothianaphthene.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.85 (2H, quartet, J=6.5 Hz); 6.68 & 7.00 (each 1H, both doublets, J =6.0 Hz).

PREPARATION 445-(2-Methanesulfonyloxyethyl)-4,5,6,7-tetrahydrothianaphthene

Using the same procedure as described in Preparation 28, 3.72 g of thetitle compound was obtained as an oily substance from 3.68 g of5-(2-hydroxyethyl)-4,5,6,7-tetrahydrothianaphthene (prepared asdescribed in Preparation 43).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 2.91 (3H, singlet);4.25 (2H, triplet, J =6.0 Hz); 6.73 & 7.07 each 1H, both doublets, J=5.0 Hz).

PREPARATION 455-(2-Methanesulfonyloxyethyl)-2-formyl-4,5,6,7-tetrahydrothianaphthene

Using the same procedure as described in Preparation 29, 2.29 g of thetitle compound was obtained as an oily substance from 3.51 g of5-(2-methanesulfonyloxyethyl)-4,5,6,7-tetrahydrothianaphthene (preparedas described in Preparation 44).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.06 (3H, singlet);4.19 (2H, triplet, J =6.5 Hz); 7.44 (1H, singlet); 9.88 (1H, singlet).

PREPARATION 46 Methyl5-(2-methanesulfonyloxyethyl)-4,5,6,7-tetrahydrothianaphthene-2-carboxylate

Using the same procedure as described in Preparation 30, 1.93 g of thetitle compound was obtained as an oily substance from 2.13 g of5-(2-methanesulfonyloxyethyl)-2-formyl-4,5,6,7-tetrahydrothianaphthene(prepared as described in Preparation 45).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 3.04 (3H, singlet);3.88 (3H, singlet); 4.19 (2H, triplet, J =6.5 Hz); 7.50 (1H, singlet).

EXPERIMENT 1 Inhibition of Thromboxane A₂ Synthetase

The platelet microsome fraction was separated from rabbit and from humanblood by the method of Needleman et al. [Needleman et al., Science, 193,163 (1976)].

The microsomal TXA₂ synthetase activity in the presence of various ofthe compounds of the invention at various concentrations was assayed bya modification of the method of Kayama et al. [Kayama et al.,Prostaglandins, 21, 543 (1981)] by incubating the microsome fractionswith labelled 1-[¹⁴ C] arachidonic acid at a concentration of 0.1 mM for1 minute at 22° C., to a final volume of 0.2 ml. The reaction wasterminated by the addition of 50 μM of 0.2 M citric acid, and then themixture was extracted with 1.5 ml of ethyl acetate. The extract wasconcentrated by evaporation under a stream of nitrogen gas and thensubjected to silica gel thin layer chromatography. The developingsolvent for the chromatography was a 90:8:1:0.8 by volume mixture ofchloroform, methanol, acetic acid and water. The inhibitory activity ofthe compound tested was estimated by the decrease in the radioactivityof the TXB₂ fraction (TXA₂ is hydrolysed to the more stable TXB₂). Theresults are shown in the following Tables 1 and 2 as the IC₅₀, i.e. theconcentration required to inhibit the activity of thromboxane synthetaseby 50%.

In addition the compounds of the invention, we also tested the activityof the known compound Dazoxiben, whose systematic name is4-[2-(1-imidazolyl)ethoxy]benzoic acid hydrochloride, and which isdisclosed in UK Patent Specification No. 2,038,821. The compounds of theinvention employed are as follows:

Compound A=4,5,6,7-tetrahydro-2-(1-imidazolyl)methylthianaphthene-6-carboxylicacid hydrochloride (hydrochloride of Compound No. 1-1);

Compound B =sodium4,5-dihydro-2-(1-imidazolyl)methylthianaphthene-6-carboxylate (sodiumsalt of Compound No. 2-1);

Compound C=4,5,6,7-tetrahydro-2-(1-imidazolyl)methylthianaphthene-5-carboxylicacid hydrochloride (hydrochloride of Compound No. 3-1).

The results using rabbit platelet microsomes are given in Table 1,whilst the results using human platelet microsomes are given in Table 2.

                  TABLE 1                                                         ______________________________________                                                       IC.sub.50                                                      Test Compound  (× 10.sup.-8 M)                                          ______________________________________                                        A              2.6                                                            B              1.3                                                            C              8.6                                                            Dazoxiben      10.6                                                           ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                                       IC.sub.50                                                      Test Compound  (× 10.sup.-8 M)                                          ______________________________________                                        A              3.0                                                            B              3.1                                                            Dazoxiben      76                                                             ______________________________________                                    

As can be seen from the results given above, the compounds of theinvention show a significantly greater activity than does the knowncompound Dazoxiben and, in particular, as shown in Table 2, the activityof the compounds of the invention against thromboxane synthetase derivedfrom human platelet microsomes is about 20 times higher than theactivity of Dazoxiben.

EXPERIMENT 2 Antithrombotic Activity in Rabbits

This test was carried out by a modification of the method of Silver etal. [Science, 183, 1085 (1974)]. The test animals used were maleJapanese white rabbits of approximately 3 kg body weight.

Each group of rabbits was administered orally the test compound at anappropriate dose and then, one hour after the oral administration, eachwas given 1.3 mg/kg of arachidonic acid by intravenous injection. Thetest animals were observed and sudden deaths during the test period wererecorded. The ED₅₀ was determined by Probit's method.

Unmedicated rabbits were employed as a control, without administeringany test compound, but these were all dead within several minutes afterthe injection of arachidonic acid, as a result of pulmonarythromboembolisms.

The results, in terms of the ED₅₀, are given in the following Table 3.In this Table, the compounds of the invention are identified as inExperiment 1.

                  TABLE 3                                                         ______________________________________                                        Test Compound  ED.sub.50 (mg/kg)                                              ______________________________________                                        A              0.27                                                           B              0.12                                                           Dazoxiben      1.1                                                            ______________________________________                                    

The results given above indicated an activity about 5-10 times higherthan that of the known compound Dazoxiben.

The results given above demonstrate that the compounds of the inventioninhibit thromboxane synthetase of the blood platelet microsomes ofmammals, including humans, and that they further exhibit strong andspecific inhibitory activities against the biosynthesis of TXA₂.Specifically, the biosynthesis of TXA₂ may be inhibited to the extent of50% by a concentration of the compound of the order of 10⁻⁸ molar.However, the compounds of the invention have very weak inhibitoryactivities against cyclooxygenase and against prostacyclin synthetaseand thus do not inhibit the synthesis of other prostaglandinderivatives.

We claim:
 1. A compound of formula (I): ##STR41## in which: R¹ and R²are independently selected from the group consisting of hydrogen atoms,C₁ -C₄ alkyl groups, C₆ -C₁₀ carbocyclic aryl groups and substituted C₆-C₁₀ carbocyclic aryl groups having one to three substituents selectedfrom the group consisting of substituents (a);n is 1 or 2; A² representsa group of formula --Z--Y in which Y represents 1-imidazolyl or 2-, 3-or 4-pyridyl and Z represents a methylene, ethylene, trimethylene orvinylene group or a methylene, ethylene, trimethylene or vinylene grouphaving one or two substituent selected from the group consisting ofsubstituents (b); A' represents a group of formula --W--COOH, where Wrepresents a direct bond, a methylene group, an ethylene group, avinylene group or a substituted methylene, ethylene or vinylene grouphaving one to three substituents selected from the group consisting ofsubstituents (c); A² is at the 5- or 6-position on the thianaphthenesystem; each broken line represents a single or double carbon-carbonbond between the 4 and 5 or the 6 and 7 positions, provided that, whenA² is at the 5-position, there is a single bond between the 6 and 7positions, and that, when A² is at the 6-position, there is a singlebond between the 4 and 5 positions; substituents (a): C₁ -C₄ alkylgroups, C₁ -C₄ alkoxy groups, C₂ -C₆ alkanoyloxy groups, aromaticcarboxylic acyloxy groups, C₂ -C₅ aliphatic carboxylic acylamino groups,aromatic carboxylic acylamino groups, trifluoromethyl groups, halogenatoms, nitro groups, cyano groups, amino groups, C₁ -C₄ alkylaminogroups, dialkylamino groups in which each alkyl part is C₁ -C₄, carboxygroups and esters and amides of said carboxy groups, the aromatic partsof said aromatic acyloxy and aromatic acylamino groups being C₆ -C₁₀carbocyclic aryl groups which are unsubstituted or have at least onesubstituent selected from the group consisting of C₁ -C₄ alkyl groups,C₁ -C₄ alkoxy groups and halogen atoms; substituents (b): C₁ -C₅ alkylgroups, C₃ -C₆ cycloalkyl groups, C₆ -C₁₀ carbocyclic aryl groups, andsubstituted C₈ -C₁₀ carbocyclic aryl groups having one to threesubstituents selected from the group consisting of C₁ -C₄ alkyl, C₁ -C₄alkoxy, and halogen; and substituent (c): C₁ -C₄ alkyl groups, C₆ -C₁₀carbocyclic aryl groups and substituted C₆ -C₁₀ carbocyclic aryl groupshaving one to three substituents selected from the group consisting ofC₁ -C₄ alkyl, C₁ -C₄ alkoxy and halogen; or a pharmaceuticallyacceptable salt, ester or amide wherein said esters is C₁ -C₈ alkyl,benzyl, p-nitrobenzyl, benzhydryl, (C₁ -C₄) alkoxycarbonyl-(C₁ -C₄)alkyl, (C₁ -C₄) alkoxycarbonyloxy-(C₁ -C₄) alkyl, phthalidyl, phenacyl,p-nitrophenacyl or (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester; andsaid amide is a (C₁ -C₄) alkyl amide or di-(C₁ -C₄) alkyl amide thereof.2. A compound as claimed in claim 1, having the formula (I^(v)):##STR42## wherein R¹, R², W, Y, Z, n and the broken lines are as definedin claim
 1. 3. A compound as claimed in claim 1 having the formula(I^(vi)): ##STR43## in which: Y is as defined in claim 1;the dotted linerepresents a double or single bond between the 6- and 7- positions; R¹and R² are independently selected from the group consisting of hydrogenatoms and C₁ -C₄ alkyl groups; Z represents a methylene, ethylene,trimethylene or vinylene group or a methylene, ethylene, trimethylene orvinylene group having at least one substituent selected from the groupconsisting of substituents (b'); W represents a direct bond or amethylene, ethylene or vinylene group; and substituents (b') C₁ -C₄alkyl groups, cyclohexyl groups, phenyl groups and substituted phenylgroups having one to three substituents selected from the groupconsisting of C₁ -C₄ alkyl groups, C₁ -C₄ alkoxy groups and halogenatoms.
 4. A compound as claimed in claim 3, in which:Y and the dottedlines are as defined in claim 9; R¹ and R² are independently selectedfrom the group consisting of hydrogen atoms, methyl groups and ethylgroups; Z represents a methylene group; and W represents a direct bond.5. A compound as claimed in claim 1 having the formula (I^(vii)):##STR44## in which: Y is as defined in claim 1;the dotted linerepresents a double or single bond between the 4- and 5- positions; R¹and R² are independently selected from the group consisting of hydrogenatoms and C₁ -C₄ alkyl groups; Z represents a methylene, ethylene,trimethylene or vinylene group of a methylene, ethylene, trimethylene orvinylene group having at least one substituent selected from the groupconsisting of substituents (b'); W represents a direct bond or amethylene, ethylene or vinylene group; and substituents (b') C₁ -C₄alkyl groups, cyclohexyl groups, phenyl groups and substituted phenylgroups having one to three substituents selected from the groupconsisting of C₁ -C₄ alkyl groups, C₁ -C₄ alkoxy groups and halogenatoms.
 6. A compound as claimed in claim 5, in which:Y and the dotedline are as defined in claim 11; R¹ and R² are independently selectedfrom the group consisting of hydrogen atoms, methyl groups and ethylgroups; Z represents a methylene group; and W represents a direct bond.7. A compound as claimed in claim 1, wherein is selected from the groupconsisting of4,5,6,7-tetrahydro-5-(1-imidazolyl)methylthianaphthene-2-carboxylic acidand pharmaceutically acceptable salts, esters and amides thereof.
 8. Apharmaceutical composition comprising an effective amount to inhibitTXA₂ biosynthesis of the compound of claim 1 or its pharmaceuticallyacceptable salt, ester or amide, in a pharmaceutically acceptablecarrier.
 9. A composition as claimed in claim 8, wherein said compoundhas the formula (I^(vi)): ##STR45## in which: the dotted line representsa double or single bond between the 6- and 7- positions;R¹ and R² areindependently selected from the group consisting of hydrogen atoms andC₁ -C₄ alkyl groups; Z represents a methylene, ethylene, trimethylene orvinylene group or a methylene, ethylene, trimethylene or vinylene grouphaving at least one substituent selected from the group consisting ofsubstituents (b'); W represents a direct bond or a methylene, ethyleneor vinylene group; and substituents (b ') C₁ -C₄ alkyl groups,cyclohexyl groups, phenyl groups and substituted phenyl groups havingone to three substituents selected from the group consisting of C₁ -C₄alkyl groups, C₁ -C₄ alkoxy groups and halogen atoms.
 10. A compositionas claimed in claim 9, in which:R¹ and R² are independently selectedfrom the group consisting of hydrogen atoms, methyl groups and ethylgroups; Z represents a methylene group; and W represents a direct bond.11. A composition as claimed in claim 8, wherein said compound has theformula (I^(vii)): ##STR46## in which: the dotted line represents adouble or single bond between the 4- and 5- positions;R¹ and R² areindependently selected from the group consisting of hydrogen atoms andC₁ -C₄ alkyl groups; Z represents a methylene, ethylene, trimethylene orvinylene group or a methylene, ethylene, trimethylene or vinylene grouphaving at least one substituent selected from the group consisting ofsubstituents (b'); W represents a direct bond or a methylene, ethyleneor vinylene group; and substituents (b') C₁ -C₄ alkyl groups, cyclohexylgroups, phenyl groups and substituted phenyl groups having one to threesubstituents selected from the group consisting of C₁ -C₄ alkyl groups,C₁ -C₄ alkoxy groups and halogen atoms.
 12. A composition as claimed inclaim 11, in which:the dotted line are as defined in claim 11; R¹ and R²are independently selected from the group consisting of hydrogen atoms,methyl groups and ethyl groups; Z represents a methylene group; and Wrepresents a direct bond.
 13. A pharmaceutical composition comprising aneffective amount to inhibit TXA₂ biosynthesis of the compound of claim 2or its pharmaceutically acceptable salt, ester or amide, in apharmaceutically acceptable carrier.
 14. A composition as claimed inclaim 8, in which said compound is selected from the group consistingof:
 4. 5,6,7-tetrahydro-5-(1-imidazolyl)methylthianaphthene-2-carboxylicacid; ora pharmaceutically acceptable salt, ester or amide thereof. 15.A method for treatment or prophylaxis of thrombosis which comprisesadministering an effective amount of the compound of claim 1 or itspharmaceutically acceptable salt, ester or amide.
 16. A method asclaimed in claim 15, in which said compound is selected from the groupconsisting of: 4.5,6,7-tetrahydro-5-(1-imidazolyl)methylthianaphthene-2-carboxylic acid;ora pharmaceutically acceptable salt, ester or amide thereof.